Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 201, 207, 314, 514, 515, 601, 607, and 1271

[Docket No. FDA-2005-N-0464 (formerly Docket No. 2005N-0403)]

RIN 0910-AA49

Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Final rule.

SUMMARY:

The Food and Drug Administration (FDA) is amending its regulations governing drug establishment registration and drug listing. These amendments reorganize, modify, and clarify current regulations concerning who must register establishments and list human drugs, human drugs that are also biological products, and animal drugs. The final rule requires electronic submission, unless waived in certain circumstances, of registration and listing information. This rulemaking pertains to finished drug products and to active pharmaceutical ingredients (APIs) alone or together with one or more other ingredients. The final rule describes how and when owners or operators of establishments at which drugs are manufactured or processed must register their establishments with FDA and list the drugs they manufacture or process. In addition, the rule makes certain changes to the National Drug Code (NDC) system. We are taking this action to improve management of drug establishment registration and drug listing requirements and make these processes more efficient and effective for industry and for us. This action also supports implementation of the electronic prescribing provisions of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) and the availability of current drug labeling information through DailyMed, a computerized repository of drug information maintained by the National Library of Medicine.

DATES:

This rule is effective on November 29, 2016. See section IV for compliance dates.

FOR FURTHER INFORMATION CONTACT:

For information pertaining to human drug products:

Paul Loebach, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 2262, Silver Spring, MD 20993, 301-796-2173.

For information pertaining to human biological drug products or human cells, tissue, and cellular and tissue-based products (HCT/Ps) regulated solely under section 361 of the Public Health Service Act:

Stephen Ripley, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993, 240-402-7911.

For information pertaining to animal drug products:

Charise Kasser, Center for Veterinary Medicine (HFV-212), Food and Drug Administration, 7519 Standish Pl., Rm. 2626, Rockville, MD 20855, 240-402-6816; or Isabel Pocurull, Center for Veterinary Medicine (HFV-226), Food and Drug Administration, 7519 Standish Pl., Rm. 2636, Rockville, MD 20855, 240-402-5877.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary

Purpose of the Regulatory Action

Summary of the Major Provisions of the Regulatory Action

Benefits and Costs

I. Background

II. Overview of the Final Rule Including Changes to the Proposed Rule

A. Overview

B. Changes to the Proposed Rule

III. Comments on the Proposed Rule

A. Labeling (§§ 201.2 and 201.25)

B. General Information (Part 207, Subpart A)

C. Registration (Part 207, Subpart B)

D. National Drug Code (Part 207, Subpart C)

E. Listing (Part 207, Subpart D)

F. Electronic Format for Registration and Listing (Part 207, Subpart E)

G. Miscellaneous (Part 207, Subpart F)

H. Human Cells, Tissues, and Cellular and Tissue-Based Products (Part 1271)

IV. Compliance Dates

V. Legal Authority

VI. Analysis of Environmental Impact

VII. Economic Analysis of Impacts

A. Introduction

B. Summary of Benefits and Costs

C. Response to Comments on the Preliminary Impact Analysis of the Proposed Rule

VIII. Paperwork Reduction Act of 1995

A. Registration Information Collection Under Part 207

B. Listing Information Collection Under Part 207

C. Registration and Listing Information Collection Under Part 607

D. Registration and Listing Information Collection Under Part 1271

E. Waiver Request Information

F. Public Disclosure Exemption Requests

G. Standard Operating Procedure for Electronic Submission

H. Capital Costs

IX. Federalism

X. References

Executive Summary

Purpose of the Regulatory Action

This final rule amends FDA's longstanding regulations governing drug establishment registration and drug listing. The amendments are aimed at modernizing these regulations and improving efficiency and reliability for FDA and drug manufacturers. These amendments also bring FDA's regulations governing drug establishment registration and listing into conformance with section 510 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 360) as amended by the Food and Drug Administration Amendments Act (FDAAA) (Pub. L. 110-85) and the Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144).

Since the 1962 Kefauver Harris amendments to the FD&C Act (Pub. L. 87-781), drug manufacturers have been required to register their establishments with FDA annually. Among other things, drug establishment registration identifies establishments for inspection by FDA. In 1973, the FD&C Act was further amended to require each registered establishment to submit a list of drugs it manufactures. FDA's regulations implementing these requirements are found in part 207 (21 CFR part 207) (pertaining to drugs and biological products generally) and part 607 (21 CFR part 607) (pertaining to blood and blood products). Manufacturers of HCT/Ps register and list either under part 207, part 807 (21 CFR 807), or under part 1271 (21 CFR part 1271), issued under authority of the Public Health Service Act (PHS Act), depending on the type of HCT/P product they manufacture.

The amendments to parts 207 and 607 adopted by this final rule modernize those regulations and bring them into conformance with section 510 of the FD&C Act following recent amendments.

Summary of the Major Provisions of the Regulatory Action

This final rule requires electronic submission, unless waived in certain circumstances, of drug establishment registration and listing information. The electronic submission requirement is consistent with FDAAA and with current practice.

The rule makes clear that the establishment registration and listing obligation rests with persons who manufacture, repack, relabel, or salvage drug products. The rule does not require persons who act only as private label distributors of drug products to register establishments or list drugs, but allows them to submit drug listing information as agents acting on behalf of persons who manufacture, repack, relabel, or salvage drug products. The amendments make several adjustments to the timing and substance of the submission of information to register a drug establishment and list drugs manufactured, repacked, relabeled, or salvaged at the establishment. The amendments also update longstanding regulatory provisions governing FDA disclosure of drug registration and listing information, stating that with certain exceptions, establishment registration and drug listing information is generally available for public disclosure.

This final rule does not include certain aspects of the proposed rule that were opposed by many who submitted comments. Features of the proposed rule that have not been finalized include most significantly: (1) A requirement that FDA, not registrants, develop national drug codes (NDCs) for assignment to listed drugs and (2) a requirement that the NDC appear in human-readable form on the label of each listed drug and provisions that would have defined the appropriate NDC for that purpose. As discussed in section III, revisions to the FD&C Act require human-readable NDCs on certain drug labels.

Benefits and Costs

All incremental costs from the final rule are one-time costs, except for registrants' annually recurring costs of certifying no change to listings upon annual registration for part 207 registrants. We estimate one-time total costs of $59.7 million and recurring costs of $0.5 million. These costs represent total annualized costs of $9 million when calculated at a 7-percent discount rate over 10 years, and $7.5 million when calculated using a 3-percent discount rate. The largest cost elements will be for registrants reading and understanding the final rule and making changes to their standard operating procedures.

Summary of Total Incremental Cost of the Final Rule

[$ millions]

Affected firms

One-time costs

Recurring costs

(annual)

Total costs annualized at 7%

Total costs annualized at 3%

Drugs and biological products (part 207)

$48.9

$0.5

$7.5

$6.2

Human blood products (part 607)

5.1

N/A

0.7

0.6

Human cell and tissue products (part 1271)

5.7

N/A

0.8

0.7

Total

1

59.7

0.5

9.0

7.5

1

Total costs are annualized over a 10-year period. Recurring costs include only annual time costs of certifying that there are no changes to listings; these costs are unique to part 207. All estimates reflect rounded 2014 dollars.

By codifying the statutory requirements of FDAAA and FDASIA, the final rule clarifies and completes the modernization of our electronic registration and listing systems. Thus, the final rule will improve management of the establishment registration and drug listing requirements and make these processes more efficient and effective for industry and for us. The final rule also supports implementation of the electronic prescribing provisions of the MMA and the availability of current drug labeling information through DailyMed, a computerized repository of drug information maintained by the National Library of Medicine.

I. Background

In the

Federal Register

of August 29, 2006 (71 FR 51276), FDA proposed to amend its regulations governing drug establishment registration and drug listing in part 207 (proposed rule). The proposed rule included ancillary amendments to parts 20, 201, 314, 514, 515, 601, 607, and 1271 (21 CFR parts 20, 201, 314, 514, 515, 601, 607, and 1271). These amendments reorganize, modify, and clarify current regulations concerning who must register establishments and list human drugs, human drugs that are also biological products, and animal drugs. The proposed rule and the final rule both specify that drug establishment registration and drug listing information generally must be submitted to FDA electronically.

After the proposed rule was published, FDAAA was adopted into law. FDAAA amended section 510(p) of the FD&C Act to require electronic submission of drug establishment registration and listing information, unless FDA waives the electronic submission requirement in individual cases. In June 2009, FDA announced publication of a guidance for industry on “Providing Regulatory Submissions in Electronic Format—Drug Establishment Registration and Drug Listing” consistent with FDAAA (74 FR 26248, June 1, 2009, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs)) (the electronic registration and listing guidance). This guidance applied to establishment registration and listing required under part 207. It did not apply to information required solely under part 607 (blood and blood products), part 807 (devices), or part 1271 (human cells, tissues, and cellular and tissue-based products). FDA generally stopped receiving drug establishment registration and listing information required under part 207 submitted on paper in June 2009, allowing paper submissions only if supported by a waiver from the electronic submission requirement in individual cases. This final rule is consistent with the electronic submission provisions of FDAAA.

FDASIA made further amendments to section 510 of the FD&C Act in 2012 to specify that:

• Annual registration of establishments takes place during the period beginning on October 1 and ending on December 31.

• The information registrants supply for annual registration includes a Unique Facility Identifier (UFI) for the establishment and includes a point-of-contact email address.

This final rule includes changes to the proposed rule consistent with these statutory provisions. The electronic registration and listing guidance stated that FDA intended to use the Data Universal Numbering System (DUNS) number, assigned and managed by Dun

& Bradstreet, as a registration number. In 2014, FDA announced publication of a guidance for industry on “Specifications of the Unique Facility Identifier (UFI) System for Drug Establishment Registration,” (79 FR 65977, November 6, 2014, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs)), in which FDA specified the DUNS number as the preferred UFI.

II. Overview of the Final Rule Including Changes to the Proposed Rule

A. Overview

The final rule adopts significant amendments to FDA's regulations governing drug registration and listing. It modernizes these regulations to require electronic submission of drug establishment registration and listing information and to otherwise match current statutory requirements and FDA's information needs.

The final rule:

• Makes minor technical amendments to §§ 20.100, 20.116, and 201.1 (updating citations to regulations in part 207).

• Removes from § 201.2 a statement about the manner in which NDCs are displayed on drug labels.

• Amends § 201.25 to allow an FDA Center Director to approve an additional bar code standard or format.

• Revises part 207 significantly.

• Amends § 314.81(b)(3)(iv) (requiring holders of approved new drug applications (NDAs) to report the withdrawal of approved drug products from sale) to make it consistent with part 207.

• Makes a minor conforming amendment to § 314.125(b)(11) (stating FDA may refuse to approve a new drug application if the drug will be manufactured in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the FD&C Act and part 207).

• Adds new § 514.111(a)(12) stating FDA will refuse to approve a new animal drug application if the drug will be produced in whole or in part in an establishment that is not registered and is not exempt from registration under section 510 of the FD&C Act and part 207.

• Makes a minor technical amendment to § 515.10(b)(8), updating a reference to the regulations in part 207.

• Adds new § 601.2(f) requiring holders of biologics license applications (BLAs) to report to FDA electronically in accordance with part 207 the withdrawal from sale of licensed biological products.

• Amends part 607 (ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS) consistent with the amendments to part 207, to require electronic submission of establishment registration and listing information.

• Amends part 1271 (HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS) to require electronic submission of establishment registration and listing information, to state that manufacturers of HCT/Ps that are regulated as drugs, devices, and/or biological products under section 351 of the PHS Act (42 U.S.C. 262) or under the FD&C Act are subject to registration and listing under part 207 or part 807, and to make other revisions consistent with the amendments to part 207.

B. Changes to the Proposed Rule

The final rule has been revised in response to comments received on the proposed rule. Our responses are discussed in section III. The final rule also includes several minor editorial revisions. The final rule makes the changes summarized in table 1.

Table 1—Substantive Changes From the Proposed Rule to the Final Rule

21 CFR Section in final rule

Description of change from proposed rule

201.2

Labeling.

• Does not include proposed revisions to § 201.2 requiring human-readable NDCs on labels.

201.25

Bar code label requirements.

• Revises § 201.25(c)(1) to accommodate alternatively formatted NDCs in bar codes.

• Does not include other proposed amendments to § 201.25.

207.1

Definitions.

• Includes definitions for the terms “finished drug product,” “unfinished drug product,” “bulk drug substance,” “private label distribution,” “registrant,” and “outsourcing facility” not included in the proposed rule.

• States that the definitions and interpretations of terms in sections 201 (21 U.S.C. 321) and 510 of the FD&C Act apply to the terms used in part 207, if not otherwise defined in § 207.1.

• Includes revised definitions of the terms “active pharmaceutical ingredient,” “commercial distribution,” “content of labeling,” “importer,” “manufacture,” “private label distributor,” “relabel,” “repack,” and “representative sampling of any other labeling”.

207.9

Who does this part cover?

• Clarifies that private label distributors are subject to part 207 (because they must have labeler codes).

• States that all drugs regulated under a BLA, except human blood or blood products regulated under part 607, are subject to part 207 and clarifies that for this purpose certain products are not included in the phrase “human whole blood and blood products”.

• States that HCT/Ps regulated as drugs under section 505 of the FD&C Act (21 U.S.C. 355) or section 351 of the PHS Act are subject to part 207.

207.13

Who is exempt from the registration and listing requirements?

• Generally exempts from registration and listing individuals or establishments engaged solely in recovering cells or tissues to become components of a biological product at a registered establishment.

• Eliminates a reference to salvagers of inactive ingredients because salvaging, as defined, is performed only on finished drug products.

• Revises § 207.13 to clarify the applicability of part 207 to medicated feeds.

• Revises § 207.13 to remove a reference to HCT/Ps made unnecessary by revisions to § 207.9.

• Adds an exemption for outsourcing facilities registered under section 503B of the FD&C Act (21 U.S.C. 353b) so as to avoid duplicative registration for those entities.

• Retains the previous establishment registration exemptions for certain drugs entering foreign trade zones and certain drugs imported for export.

207.17

Who must register?

• Revises § 207.17(b) to state that FDA will accept establishment registration or listing information submitted by a private label distributor if it is acting as an authorized agent for an establishment that manufactures, repacks, relabels, or salvages drugs.

207.25

What information is required for registration?

• Revises proposed § 207.25 to include the UFI required as part of establishment registration under FDASIA.

207.29

What are the requirements for reviewing and updating registration information?

• Revises § 207.29 to specify that registrants must review and update registration information between October 1 and December 31 each year, consistent with FDASIA.

207.33

What is the National Drug Code (NDC), how is it assigned, and what are its requirements?

• Allows for 10- or 11-digit NDCs, consistent with a longstanding statement in § 207.35(b)(2)(i), as it read prior to this final rule, that FDA will expand the NDC labeler code from 5 to 6 numeric characters when the available 5-character code combinations are exhausted.

• States that registrants will propose NDCs for assignment by FDA.

• Includes formatting requirements for registrants to follow when formulating their own proposed NDCs.

• Allows for alternatively formatted NDCs for certain HCT/Ps.

• Explains how a labeler code can be obtained.

• Allows registrants to reserve an NDC for a drug product under development.

• Eliminates proposed § 207.33(c). (What information must a manufacturer submit before we will assign an NDC number to a drug?)

• Adds some information elements described in proposed § 207.33(c) to the drug listing information now described in § 207.49 (Added to the listing information required under § 207.49 are the names of inactive ingredients in the listed drug and in the case of an unfinished drug, the number assigned to the Drug Master File or Veterinary Master File, if any, that describes the manufacture of the drug).

• The option to submit an approved U.S. application number instead of a list of inactive ingredients for a finished drug product (as proposed in § 207.33(c)) is not retained in § 207.49 of this final rule.

207.35

What changes require a new NDC?

• Introduces new § 207.35 to more clearly explain what changes to drugs require a new NDC and does not include inactive ingredient changes in this section.

207.37

What restrictions pertain to the use of the NDC?

• Revises § 207.37 to state that a product may be deemed to be misbranded if an NDC is used improperly.

207.41

Who must list drugs and what drugs must they list?

• Revises § 207.41 to clarify the manner in which human drugs that are manufactured, repacked, or relabeled for private label distribution are listed.

207.45

When, after initial registration of an establishment, must drug listing information be submitted?

• Revises § 207.45 to state that drug listing must take place no later than 3 calendar days after initial registration of an establishment, rather than “at the time of” initial registration.

207.49

What listing information must a registrant submit for a drug it manufactures?

• Revises § 207.49 to reflect that registrants will propose their own NDCs under the final rule.

• Eliminates the requirement of proposed §§ 207.49(f), 207.53(c), and 207.54(b)(4) (which would have required foreign establishments to identify importers when listing drugs they manufacture, repack, relabel, or salvage). (This is now reported only as establishment registration information for foreign establishments.).

• Expands the language of proposed § 207.49(d) (now § 207.49(a)(11)) to make clear that a registrant's own establishment(s) must be identified in drug listing information as well as other establishments involved in the production of unfinished drugs received by the registrant and to require identification of all such establishments using their UFIs.

• Removes from proposed § 207.49 the option to provide an approved U.S. application number instead of labeling.

• Revises § 207.49 (also §§ 207.1 and 207.53) to categorize certain drug products according to whether they are subject to sections 505 or 512 of the FD&C Act (21 U.S.C. 355 or 360b) or section 351 of the PHS Act, rather than whether registrants regard them as subject to those provisions.

• Adds §§ 207.49(a)(15)(iv) and 207.53(d)(4) to require the submission of labels for listed drugs not elsewhere described in §§ 207.49(a)(14) and 207.53(d).

• Clarifies in new §§ 207.49(a)(15) and 207.53(f) the information a registrant must submit when listing a human drug manufactured for private label distribution.

• Adds § 207.49(b) to describe drug listing information that is requested of registrants but not required.

• Adds § 207.49(a)(2) so that drug listing information includes package size and type.

207.53

What listing information must a registrant submit for a drug that it repacks or relabels?

• Shifts from proposed § 207.33(d)(1)(iii) to new § 207.53(b) the requirement that for a repacked or relabeled drug, registrants identify the NDC assigned to the finished drug received by the registrant for repacking or relabeling and exempts repackaged medical gases from this requirement.

• Requires identification of establishments where repacking, or relabeling is performed based on their UFIs rather than by their registration numbers.

• Clarifies that all current labeling (new labeling) for a repacked or relabeled drug must be submitted, not only the changed labeling.

• Specifies that for animal drugs subject to section 512 of the FD&C Act, all current

labeling

is submitted, whereas a copy of the current

label,

and other information, is submitted for other animal drugs.

207.54

What listing information must a registrant submit for a drug that it salvages?

• Requires identification of establishments where salvaging is performed by their UFIs rather than by their registration numbers.

• Deletes references to salvaged drugs distributed by private label distributors.

207.57

What information must registrants submit when updating listing information and when?

• Revises proposed § 207.57 to improve clarity and to delete the proposed requirement that registrants routinely update information provided under § 207.55.

• Allows registrants to submit a blanket “no changes” certification applicable to listing information they have previously submitted electronically, rather than making product-by-product “no changes” certifications for individual listed drugs.

207.61

How is registration and listing information provided to FDA?

• Revises § 207.61 to improve clarity, to state that we may periodically issue guidance on electronic registration and listing, and to clarify that when foreign language labeling is used under § 201.15(c), the content of labeling must be submitted in that foreign language along with an accurate English translation.

• Removes the option to submit advertisements and certain labeling in paper format, consistent with the electronic submission requirement of section 510(p) of the FD&C Act, as amended by FDAAA.

207.65

How can a waiver of the electronic submission requirement be obtained?

• Clarifies that requests for waivers of the electronic submission requirement cannot be relied upon until FDA grants them.

• States more broadly the conditions under which FDA will grant waiver requests.

• Specifies that waiver requests must be submitted in writing and must state reasons why electronic submission is not reasonable for the registrant.

• States that FDA will specify terms of waivers and may limit their duration.

207.69

What are the requirements for an official contact and a United States agent?

• Revises proposed § 207.69 to state that designated official contacts and United States agents are both responsible for reviewing, disseminating, routing, and responding to all communications from FDA, including emergency communications.

207.77

What legal status is conferred by registration and listing?

• Includes minor revisions to improve clarity and mentions the UFI that will be used to identify establishments.

207.81

What registration and listing information will FDA make available for public disclosure?

• Reorganizes § 207.81 so that registration and listing information that will be disclosed is described in paragraph (a), and exceptions are described in paragraphs (b) and (c).

• Categorizes updated drug listing information submitted under § 207.57 as generally disclosable.

• Adds § 207.81(b)(2) to make explicit that FDA will generally not disclose the names of inactive ingredients in listed drug products if the registrant makes a valid assertion of confidentiality.

• Categorizes the information submitted to reserve an NDC under new § 207.33(d)(3) as generally not disclosable.

• Categorizes the identities of the establishments involved in manufacturing, repacking, relabeling, or salvaging listed drugs as generally not disclosable.

• Categorizes as generally not disclosable the NDC assigned to an unfinished drug received by a registrant for use in the manufacture of a listed drug reported under § 207.49(a)(12) (

i.e.

, the association between the unfinished drug and the listed drug is generally not disclosable).

• No longer categorizes the NDC assigned to a drug immediately before it is received by a registrant for salvaging as generally not disclosable (because the NDC assigned to a drug does not change when a drug is merely salvaged and not also repackaged or relabeled).

314.81

Other postmarketing reports (reporting the discontinuation of a drug that is the subject of an approved NDA).

.

• Renumbers proposed § 314.81(b)(3)(iii) as § 314.81(b)(3)(iv) and revises this section to provide for electronic or written submissions in certain circumstances, under both paragraphs (a) and (b).

601.2(f)

Applications for biologics licenses (reporting the discontinuation of a drug that is licensed under a BLA).

• Revises proposed § 601.2(f) to reference the electronic submission requirement of § 207.61 and the waiver provision of § 207.65 and to clarify that the date on which the product is expected to be no longer in commercial distribution must be reported rather than the “date of withdrawal from sale”.

607.1

Scope (Establishment registration and product listing for manufacturers of human blood and blood products.)

• Adds a new scope provision (§ 607.1) to part 607 for clarity.

607.3

Definitions (Establishment registration and listing for blood and blood products).

• Adds a definition of “foreign”.

• Revises the proposed definition of “importer”.

607.22

How to register blood product establishments and list blood products.

• Revises proposed § 607.22 to remove references to Form FDA 2830 and to state that blood product establishment registration and blood product listing must be transmitted to FDA electronically through the Blood Establishment Registration and Product Listing system, unless FDA waives the electronic submission requirement in individual cases.

607.25

Information required for establishment registration and blood product listing.

• Removes references to Form FDA 2830.

• Requires submission of a UFI when registering blood and blood product establishments along with a registration number if previously assigned by FDA.

• Adds the UFI of the parent establishment to blood product listing information required under § 607.25(b)(3).

607.26

Amendments to establishment registration.

• Revises § 607.26 regarding amendments to establishment registration to reference the Blood Establishment Registration and Listing System in place of Form FDA 2830.

• Clarifies that 5 days refers to 5 calendar days in this section.

607.30

Updating blood product listing information.

• Revises § 607.30 regarding updates to blood product listing information to reference the Blood Establishment Registration and Listing System in place of Form FDA 2830.

607.37

Public disclosure of establishment registration and blood product listing information.

• Revises § 607.37 to remove references to Form FDA 2830.

• Structures § 607.37 in a way that matches § 207.81 (public disclosure of drug registration and listing information).

607.40

Establishment registration and blood product listing requirements for foreign blood product establishments.

• Retains the exemptions applicable to foreign trade zones and products imported under section 801(d)(4) of the FD&C Act (21 U.S.C. 381(d)(4)).

• Revises proposed § 607.40 to state more broadly the circumstances under which FDA will waive the electronic submission requirement for foreign blood product establishments.

607.80

Applicability of part 607 to licensed devices.

• Adds a new § 607.80 clarifying the applicability of part 607 to certain licensed devices.

1271.1

What are the purpose and scope of this part? (HCT/Ps)

• Adds the word “electronic” in place of “unified” in § 1271.1.

1271.3

How does FDA define important terms in this part?

• Revises the definition of “importer” in proposed § 1271.3(mm) to include “at the time of entry”.

1271.20

If my HCT/Ps do not meet the criteria in § 1271.10, and I do not qualify for any of the exceptions, what regulations apply?

• Adds a further amendment to § 1271.20 to indicate that subpart B of part 1271 (procedures for registration and listing) does not apply to HCT/Ps that do not meet the criteria set out in § 1271.10(a). (In other words, HCT/Ps not regulated solely under section 361 of the PHS Act are subject to registration and listing under part 207 or part 807 rather than part 1271.)

1271.25

What information is required for establishment registration and HCT/P listing?

• Removes from proposed § 1271.25(a)(6) the requirement that each foreign HCT/P establishment designate only one United States agent.

• Removes a reference to Form FDA 3356 in proposed § 1271.25(c)(4).

• Revises proposed § 1271.25(d) to clarify that it pertains to HCT/Ps regulated under BLAs and to state that establishment registration and listing information for such products must be submitted in accordance with the electronic submission requirements of part 207, subpart E.

This final rule does not include the proposed amendments to §§ 330.1, 610.60, and 610.61, all of which dealt with NDCs on labels. This final rule also does not include the proposed minor amendment to § 1271.37 (regarding public disclosure of HCT/P establishment registration and listing information) in light of the technical amendments adopted on April 3, 2015 (80 FR 18087).

Some changes from the proposed rule not addressed in section III (Comments on the Proposed Rule) are addressed in the following paragraphs.

Active pharmaceutical ingredient:

To prevent confusion, we proposed to replace the term “bulk drug substance” with the more descriptive term “active pharmaceutical ingredient.” This change is retained in the final rule. Sections 503A(b)(1)(A) and 503B(a)(2) of the FD&C Act (21 U.S.C. 353a(b)(1)(A) and 353b(a)(2)), however, refer specifically to the definition of “bulk drug substance” within part 207. To ensure conformity with the FD&C Act, both “bulk drug substance” and “active pharmaceutical ingredient” are defined in § 207.1 of the final rule. As intended by the proposed rule, “active pharmaceutical ingredient” will have the same meaning as “bulk drug substance.”

Salvage:

In this final rule, the term “salvage” is defined to mean the act of segregating out those finished drug products that may have been subjected to improper storage conditions (such as extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation) for the purpose of returning the products to the marketplace and includes applying manufacturing controls such as those required by current good manufacturing practice in parts 210 and 211 (21 CFR parts 210 and 211). Substantively, this matches the definition of “drug product salvaging” included in the proposed rule, but the words have been rearranged for greater clarity. This final rule also includes a definition for the term “salvager.”

Establishment registration number and Unique Facility Identifier:

We proposed to define the term “establishment registration number” in § 207.1 to mean “the number assigned by FDA to the establishment during the establishment registration process required in this part.” The final rule changes the definition of “establishment registration number” slightly to state that the number is assigned “after” the registration process, rather than “during.”

The establishment registration number identifies establishments for inspection by FDA. Historically, an establishment registration number is assigned to each establishment of each manufacturer, repacker, relabeler, or salvager after the initial registration, when such activities begin. In the preamble to the proposed rule, we explained that “[c]urrently, the FDA Establishment Identifier (FEI) will be the number we assign as the establishment registration number. In the future, however, we may use a different number as the establishment registration number” (71 FR 51276 at 51288).

After the proposed rule was published, FDASIA amended section 510 of the FD&C Act to require persons subject to the drug establishment registration requirement to submit a UFI. In the electronic registration and listing guidance, FDA stated that it intended to use the DUNS number, assigned and managed by Dun & Bradstreet, as a registration number. To implement the UFI provision of FDASIA, FDA also issued guidance in 2014 that specified the DUNS number as the preferred UFI.

1

1

See the guidance for industry “Specification of the Unique Facility Identifier (UFI) System for Drug Establishment Registration,” November 2014, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs).

Under the final rule, the establishment registration number and the UFI are two distinct numbers. For now, FDA will continue to assign an FEI as the establishment registration number after an establishment is registered for the first time. The final rule requires registrants to submit the establishment registration number (currently the FEI), “if previously assigned by FDA,” under § 207.25. Someone registering an establishment for the first time is not expected to have a registration number for the establishment. Such a registrant is required to submit its registration number at the time of the first annual review and update of registration information under § 207.29(b) of this final rule and is encouraged to submit the registration number sooner, as soon as it is received from FDA. The establishment registration number does not need to be submitted at the time of each annual registration update under § 207.29 unless the establishment registration number has changed. Likewise, the UFI, currently specified as

the DUNS number, must be submitted when registering an establishment for the first time under § 207.25. The UFI does not need to be submitted at the time of each annual registration update under § 207.29 unless the UFI has changed.

Bar code label requirements (§ 201.25):

As explained in section III, this final rule does not include two proposed amendments to § 201.25. It does, however, include a minor new amendment to § 201.25. To accommodate the possibility of alternatively formatted NDCs in bar codes, § 201.25 is amended in this final rule to allow FDA's Center Directors to approve additional standards or formats for bar codes.

Submission of approved U.S. application number instead of inactive ingredients (§ 207.33(c)(2)):

Information registrants would have submitted under § 207.33(c) of the proposed rule to obtain an NDC has been shifted to drug listing information required under § 207.49 of this final rule. Under § 207.49(a)(5) of this final rule, a registrant must provide the name of each inactive ingredient in a listed drug it manufactures. The option to submit an approved application number instead of a list of inactive ingredients is not retained in the final rule because FDA is not currently able to pull inactive ingredient information from approved applications to our drug listing systems.

III. Comments on the Proposed Rule

In the

Federal Register

of October 31, 2006 (71 FR 63726), FDA announced an extension of the comment period for this rulemaking and a public meeting to discuss the proposed changes to the NDC system presented in the proposed rule. The public meeting was held on December 11, 2006. In the

Federal Register

of February 8, 2007 (72 FR 5944), FDA announced a reopening of the comment period because technical problems prevented some persons from submitting comments electronically on the last day of the previous comment period. The Agency received numerous comments, including oral presentations made at the December 2006 public meeting and approximately 200 written comments placed in the docket. Comments were received from prescription and nonprescription drug manufacturers and related companies, trade associations representing drug manufacturers and other interested parties, academic institutions, and professional associations.

The docket for this rulemaking, Docket No. FDA-2005-N-0464, was also used to collect comments on FDA's draft guidance for industry entitled “Providing Regulatory Submissions in Electronic Format—Drug Establishment Registration and Drug Listing” (74 FR 26248). In this final rule, we are responding to comments that pertain to the rulemaking,

i.e.,

comments that relate to the changes in regulations proposed on August 29, 2006.

To make it easier to identify comments and our responses, the word “Comment,” in parentheses, appears before the comment's description, and the word “Response,” in parentheses, appears before our response. We have numbered each comment to help distinguish between different comments. Similar comments are grouped together under the same number. The number assigned to each comment is purely for organizational purposes and does not signify the comment's value or importance or the order in which comments were received.

A. Labeling (§§ 201.2 and 201.25)

The proposed rule included amendments to § 201.2 that would have required drugs subject to the listing requirement of part 207 to have labels that bear the appropriate NDC in human-readable form. As discussed in this document, this final rule does not include the proposed amendments that would have made human-readable NDCs mandatory on drug labels.

Section 201.2 currently states that NDCs are “requested but not required” to appear on all drug labels. Section 201.25 currently requires bar codes on prescription human drug labels with certain exceptions and on certain nonprescription human drug labels. Section 201.25(c) currently specifies that each bar code must contain, at a minimum, the appropriate NDC.

Sections 201.2 and 201.25 currently do not specify which NDC should appear on labels and in bar codes apart from referring to it as “the appropriate” NDC (§ 201.25(c)). This implies that the NDC appearing on a drug's label match an NDC under which the drug is appropriately listed under part 207.

1. NDC Numbers (§ 201.2)

Pharmacists and health care providers use NDCs currently appearing on drug labels in a variety of ways, including to help prevent medication errors and to process prescription drug reimbursement claims. We believe there is currently a high level of cooperation with FDA's request in § 201.2 that NDCs appear in human-readable form on labels, as drug manufacturers recognize the importance of this information.

In addition to making human-readable NDCs on drug labels mandatory, the proposed rule would have specified which NDC must appear on labels. Specifically, proposed § 201.2(b) sought to define the appropriate NDC for this purpose as being that of the last manufacturer, repacker, relabeler, or private label distributor responsible for the drug immediately before it is received by the wholesaler or retailer.

(Comment 1) Several comments recognized the importance of having NDCs in human-readable form on labels, but many objected to FDA's proposed provisions defining the appropriate NDC in proposed § 201.2(b). In particular, certain repackers objected to the proposed requirement that a repacker's NDC, rather than that of the original manufacturer, appear on the labels of repackaged drug products.

(Response) This final rule does not include the proposed amendments to § 201.2 that would have made human-readable NDCs mandatory on drug labels. It includes only a conforming amendment to that section (replacing the reference to § 207.3(b)(3) with an updated reference to new § 207.1).

The Drug Quality and Security Act (DQSA) (Pub. L. 113-54) of 2013 includes as Title II the Drug Supply Chain Security Act (DSCSA). The DSCSA requires drug manufacturers and repackagers (as defined in sections 581(10) and 581(16) of the FD&C Act, respectively) to affix or imprint a

product identifier

on packages for certain prescription drugs for human use. Under section 581(14) of the FD&C Act, a “product identifier” is a standardized graphic that includes, in both human-readable form and on a machine-readable data carrier, the “standardized numerical identifier,” lot number, and expiration date of the product. The NDC is one component of the standardized numerical identifier. FDA has determined that because the DSCSA requires the inclusion of NDCs on certain prescription drug labels (as part of a product identifier), it is unnecessary to include the proposed amendments to § 201.2 in this final rule.

Our determination that the proposed amendments to § 201.2 should not be finalized renders moot many comments concerning identification of the appropriate NDC for labeling purposes, along with placement and formatting issues. Therefore, we do not respond to those comments.

The DSCSA does not require manufacturers or repackagers to affix or imprint product identifiers on nonprescription human drug products or on animal drugs. Therefore, we will maintain the status quo for those drug products, meaning FDA will continue to request that NDCs in human-readable

form appear on all drug labels and in all drug labeling, as indicated in § 201.2. We may revisit a regulatory requirement that human-readable NDCs appear on the labels of nonprescription human drug products and animal drugs in the future.

2. Bar Code Label Requirements (§ 201.25)

Section 201.25 currently requires that a human drug product's NDC be included in its bar code. We proposed to amend § 201.25 in two minor ways: (1) To add a cross-reference to proposed new § 201.2(b), which would have described the “appropriate NDC” for labeling purposes and (2) to add new § 201.25(e) stating that a bar code may be displayed on certain drug product labels voluntarily but only if it meets the requirements of § 201.25(c). Neither proposed amendment to § 201.25 is retained in the final rule.

(Comment 2) The Animal Health Institute expressed concern that proposed § 201.25(e) would unreasonably burden its members who, although they are not currently required by § 201.25 to place bar codes on animal drug labels (because it applies to human drugs), may do so for logistical reasons. They asked that the animal health industry be exempt from the requirement to include an NDC in any bar codes appearing on animal drug labels. Similar comments were received from manufacturers of allergenic extracts. Allergenic extracts are currently exempt from the bar code requirement (see § 201.25(b)(1)(i)(B)). Commenters explained that manufacturers of allergenic extracts may place bar codes on their labels for inventory, warehousing, and other logistical purposes. They objected to proposed § 201.25(e) to the extent that it would require such bar codes to include NDCs.

(Response) FDA has not retained proposed § 201.25(e) in this final rule.

(Comment 3) A group of comments asserted that 11-digit NDCs cannot be encoded into a bar code that meets European Article Number/Uniform Code Council or Health Industry Business Communications Council standards, as required by current § 201.25(c). Another comment urged FDA to remove the NDC from bar codes.

(Response) This final rule acknowledges that 10-digit NDCs will be exhausted at some point in the future as a mathematical inevitability. As discussed in our response to Comment 52, this final rule reduces the number of occasions when a change to a drug requires a new NDC under § 207.35. This final rule also amends § 201.25 to allow FDA's Center Directors to approve additional bar code standards and formats.

As discussed in response to Comment 1, the DSCSA requires the inclusion of product identifiers on prescription human drug labels and defines “product identifier” to mean a standardized graphic that includes, in both human-readable form and on a machine-readable data carrier the standardized numerical identifier, lot number, and expiration date of the product. The standardized numerical identifier, a component of the product identifier, is comprised of the NDC and a serial number.

FDA continues to recognize the importance of NDCs on drug labels in both machine-readable and human-readable form. We remind manufacturers of the current requirement in § 201.25 that bar codes on human drug labels include the appropriate NDC, and we encourage manufacturers to continue to provide the NDC in human-readable form on drug labels where not required by the DSCSA.

B. General Information (Part 207, Subpart A)

1. What definitions and interpretations of terms apply to this part? (§ 207.1)

The proposed rule included a set of terms and definitions in §§ 207.1, 607.3, and 1271.3. These definitions are retained in the final rule with several modifications. Additionally, the final rule includes definitions for the terms “finished drug product,” “unfinished drug product,” “bulk drug substance,” “outsourcing facility,” “private label distribution,” and “registrant” in § 207.1 and a definition of “foreign” in § 607.3.

a. Commercial distribution.

In the proposed rule, the definition of “commercial distribution” excluded “the internal or interplant transfer of an active pharmaceutical ingredient between registered establishments within the same parent, subsidiary, and/or affiliate company.”

In the final rule, the definition does not include the phrase “an active pharmaceutical ingredient” so that internal or interplant transfers between such registered establishments are not treated as commercial distribution under part 207, whether the transfer involves active pharmaceutical ingredients, other unfinished drug products, or finished drug products.

(Comment 4) A comment suggested that the definition of “commercial distribution” be revised to exclude transfers between a registered establishment and a marketing authorization holder when the two are in a contractual relationship. Otherwise, this comment argued, products marketed by private label distributors who employ contract manufacturers are held to a higher burden of documentation than products manufactured and distributed by the same entity.

(Response) We disagree with the suggestion that a transfer of drugs from a contract manufacturer to another contracting party should not qualify as commercial distribution. Such an exemption would interfere with FDA's ability to track drugs and establishments for inspection. However, by revising the definition of “commercial distribution” to exclude internal or interplant transfers of drugs, including active pharmaceutical ingredients, other unfinished drugs, and finished drug products, between registered establishments under common ownership and control, we have reduced the drug listing burden generally. This exclusion accommodates the common practices of specialized manufacturing at different registered establishments under common ownership and control. This practice often results in multiple internal and interplant transfers of these materials prior to marketing, which we do not consider commercial distribution for registration and listing purposes.

b. Content of labeling.

The proposed rule included a multipart definition for the term “content of labeling” with separate provisions applicable to:

• Human prescription drugs that the manufacturer regards as subject to section 505 of the FD&C Act or section 351 of the PHS Act,

i.e.,

subject to premarket approval from FDA;

• Human prescription drugs that the manufacturer regards as not subject to section 505 of the FD&C Act or section 351 of the PHS Act;

• Human nonprescription drugs; and

• Animal drugs.

The term “content of labeling” was used in the proposed rule to describe some, but not all, labeling that must be submitted with drug listing information. For example, proposed § 207.49(g)(2)(i) stated that listing information for certain human over-the-counter (OTC) drugs must include “all current labeling . . . including the content of labeling.” Content of labeling is defined in a very similar way in the final rule with deletion of the phrase “that the manufacturer regards as” and the addition of a reference to the labeling requirements for veterinary drugs in 21 CFR part 201.

We removed the language “that the manufacturer regards as subject to section 505 [or 512] of the FD&C Act or section 351 of the PHS Act” and added in its place language that refers to drugs as being either subject or not subject to those provisions. We made this change after determining that the manner in which content of labeling is defined should not depend on a manufacturer's subjective understanding or intent with respect to sections 505 or 512 of the FD&C Act or section 351 of the PHS Act.

The revised definition includes, among others, the category “human prescription drugs that are not subject to section 505 of the FD&C Act or section 351 of the PHS Act.” We have retained this construction even though FDA considers it unlikely that any currently marketed human prescription drug product is grandfathered or is otherwise not a new drug subject to those provisions. However, the Agency recognizes that the existence of such drugs is at least theoretically possible. No part of this final rule is a finding as to the legal status of any particular drug product.

Regarding animal drugs, in part four of the definition of “content of labeling” and in other places throughout this final rule, the phrase “subject to section 512” means, for purposes of this final rule, drugs meeting the definition of “new animal drug” as that term is defined in section 201(v) of the FD&C Act, and which therefore are subject to some or all of the provisions relating to new animal drugs found in section 512 of the FD&C Act. This term includes not only new animal drugs that are approved under section 512 but also new animal drugs that are conditionally approved under section 571 of the FD&C Act (21 U.S.C. 360ccc) or indexed under section 572 of the FD&C Act (21 U.S.C. 360ccc-1). The phrase “all other animal drugs” as used in provisions of this final rule at §§ 207.49(a)(15)(iii) and 207.53(d)(3) describing the labeling registrants must provide as part of the listing for an animal drug, refers to animal drugs that do not meet the definition of new animal drug found in section 201(v) of the FD&C Act (

e.g.,

grandfathered animal drugs). Although the Agency recognizes that the existence of such animal drugs is theoretically possible, we believe it is unlikely that any currently marketed animal drug product is grandfathered or otherwise not a “new animal drug” subject to section 512 of the FD&C Act.

(Comment 5) Commenters asked FDA to clarify how content of labeling differs from package inserts and final printed labeling.

(Response) A prescription human drug product's FDA-approved labeling is sometimes referred to as a “package insert” or as “professional labeling.” In defining the term “content of labeling,” for human drugs, we use the phrase “prescription drug labeling” (instead of “package insert” or “professional labeling”) to mean FDA-approved labeling for prescription drug products described in §§ 201.56, 201.57, and 201.80. For human prescription drugs that are subject to section 505 of the FD&C Act or section 351 of the PHS Act, content of labeling is defined as the content of the prescription drug labeling. For human OTC drugs, content of labeling is not defined in these terms; it includes “all text, tables, and figures including the drug facts labeling required by § 201.66.” For animal drugs, “content of labeling” is defined to mean labeling that accompanies the drug that is necessary to enable safe and proper administration of the drug. This would generally include package inserts and final printed labeling. Sections 207.49 and 207.53 require submission of labeling with drug listing information. In most cases, all current labeling must be submitted, including the content of labeling.

(Comment 6) A comment stated that FDA should more clearly delineate between the terms “label” and “labeling” throughout the rulemaking, rather than using the term “labeling” to refer to both. This comment pointed out that the proposed rule's definition of content of labeling for human OTC drugs referred to “labeling required by § 201.66,” but § 201.66 pertains to information appearing on the “outside container or wrapper of the retail package, or the immediate container label if there is no outside container or wrapper” (§ 201.66(c)).

(Response) We have clarified in § 207.1(a) of the final rule that the definitions and interpretations of terms in sections 201 and 510 of the FD&C Act apply to the terms used in part 207 unless otherwise defined. Accordingly, the term “label” means a display of written, printed, or graphic matter upon the immediate container of any article consistent with section 201(k) of the FD&C Act. The term “labeling” more broadly includes both immediate container labels and other written, printed, or graphic matter accompanying such article consistent with section 201(m) of the FD&C Act. When we intend to refer only to immediate container or package labels, we use the term “label.” More often, we use the broader term “labeling” in this final rule to encompass both immediate container labels and/or other written, printed, or graphic matter accompanying the drug, as the labeling definition in section 201(m) of the FD&C Act has been interpreted. The term “content of labeling” is defined slightly differently for human prescription drugs, human OTC drugs, and animal drugs, and the term is intended to encompass both labels and labeling.

The proposed rule (proposed § 207.1) referred only to definitions in section 510 of the FD&C Act, and the preamble to the proposed rule suggested that reference to the definitions in section 201 of the FD&C Act was intentionally omitted (71 FR 51276 at 51285). Consistent with 21 CFR 1.1(b), this final rule clarifies that the definitions in section 201 of the FD&C Act apply to the terms used in part 207.

c. Establishment.

We proposed to define “establishment” in § 207.1 as “a place of business under one management at one geographic location.” The definition in proposed § 207.1 also stated “one geographic location may include separate buildings within the same city if their activities are closely related to the same business enterprise and are under the supervision of the same local management.”

Rather than adopt this proposed definition, the final rule retains the definition of the term “establishment” that has appeared in the part 207 regulations since 1980. This definition states that an establishment is “at one general physical location.”

(Comment 7) One comment suggested that the phrase “within the same city” used in the proposed definition of “establishment” was too specific. This comment argued that a manufacturing facility located in a city with a warehouse located just outside that city should together be treated as a single establishment for registration purposes.

(Response) In reviewing this comment and considering it in light of the longstanding definition of “establishment” and the objectives behind the establishment registration requirement, we determined that the existing definition in part 207 is clearer and better serves our objectives than would the proposed amended definition. The longstanding language, “one general physical location,” generally restricts a single establishment to one street address or one or more contiguous plots of land. We do not agree with the comment that a second facility located in a different city should be covered by the first facility's establishment registration.

We note, however, that a facility operated only as a warehouse may not require registration. Section 510 of the FD&C Act and § 207.17 of this final rule

require registration of establishments where drugs are manufactured, repacked, relabeled, or salvaged. A facility at which drugs are merely stored may not require registration under this final rule, unless the facility includes, for example, controlled storage for stability testing as an element of good manufacturing practices. Other Federal and State requirements may apply to such facilities.

Likewise, the corporate headquarters of a drug establishment should not register under this rule if drugs are not manufactured, repacked, relabeled, or salvaged at that location.

d. Foreign.

We proposed to use the term “foreign” to refer to a manufacturer, repacker, relabeler, drug product salvager, or private label distributor who is located in a foreign country and who manufactures, repacks, relabels, salvages, or distributes a drug that is imported or offered for import into the United States. When used to modify “establishment,” we proposed to use “foreign” to refer to an establishment that is located in a foreign country and is the site where a drug that is imported or offered for import into the United States was manufactured, repacked, relabeled, salvaged or distributed.

We have omitted the words “or distributed” from this definition because only establishments at which drugs are manufactured, repacked, relabeled, or salvaged are required to be registered.

(Comment 8) One comment urged us to revise the definition of “foreign” to mean “located in a foreign country” while stating in § 207.9 that part 207 applies to foreign entities who import or offer for import products into the United States.

(Response) We do not agree that the proposed rule was confusing or difficult to understand in this respect and have decided against making this change.

e. Importer.

Section 207.25 of this final rule and section 510(i) of the FD&C Act require foreign establishments, when registering, to provide names and contact information for each importer in the United States of drugs manufactured, repacked, relabeled, or salvaged at the establishment that is known to the establishment. We proposed to define “importer” to mean, in part, “a company or individual in the United States that is an owner, consignee, or recipient of the foreign establishment's drug that is imported into the United States.” In proposing this language, we recognized that a foreign establishment may have more than one importer, and we proposed to include in this term any owner, consignee, or recipient, even if not the initial owner, consignee, or recipient, of the foreign establishment's drug that is imported into the United States.

(Comment 9) Some comments stated that our proposed definition of the term “importer” was too broad and would increase the burden on manufacturers to provide unnecessary information concerning a wide variety of entities that are not responsible for the drug. One comment noted that the inclusion of downstream recipients in our definition of “importer” would impose a significant reporting burden on foreign establishments that is not required of domestic establishments.

(Response) We agree that we should clarify and narrow the proposed definition of “importer.” As proposed, the definition included every U.S. recipient of a foreign-produced drug, excepting only the final consumer or patient. Of this large group, foreign establishments would be required to identify in their establishment registration submissions only those importers that are known to the establishment. To make this information element more useful to FDA and to reduce the burden on registered establishments, we have determined that in this context the term “importer” should include a U.S. owner, consignee, or recipient

at the time of the drug's entry into the United States

and should not include additional subsequent owners, consignees, or recipients of the drug. We have revised the definition of importer in § 207.1 of the final rule accordingly.

(Comment 10) One comment recommended that we change “company or individual” to “person,” in the rule's definition of “importer,” consistent with the definition of the term “person” in section 201(e) of the FD&C Act.

(Response) We agree that the term “person,” as defined in the FD&C Act, is an improvement over “company or individual” in this definition. We have made this change in §§ 207.1 and 607.3 of the final rule, and as discussed in our response to comment 6, we have also added a statement in §§ 207.1(a) and 607.3(a) that the definitions and interpretations of terms in sections 201 and 510 of the FD&C Act apply if not otherwise defined.

f. Person who imports or offers for import.

Section 207.25 of this final rule and section 510(i) of the FD&C Act also require foreign establishments, when registering, to supply names and contact information for each person who imports or offers for import drugs manufactured, repacked, relabeled, or salvaged at the establishment. The proposed rule's definition of “person who imports or offers for import” included “an agent, broker, or other entity, other than a carrier, that the foreign establishment uses to facilitate the import of its drug into the United States.” We invited comments on the use and interpretation of the term “facilitate.”

(Comment 11) Some comments expressed concern regarding the potential breadth of this definition, noting in particular that the word “facilitate” could, in theory, encompass entities such as foreign insurance adjusters, underwriters, and international banks. Commenters pointed out the significant burden associated with the identification of such entities in foreign establishment registrations and updates to registrations, noting that international supply chains and business relationships are not static. One comment urged FDA to exclude customs brokers from the rule's definition of “person who imports or offers for import.” Another comment encouraged FDA to exclude middlemen from this definition, as their identities would change frequently.

(Response) Although we did not intend for the word “facilitate” to be read as broadly as some comments suggested, FDA agrees that the definition of “person who imports or offers for import” should be made more precise, narrow, and useful.

We note, as a matter of clarification, that in section 510(i) of the FD&C Act and in § 207.25 of the final rule, the requirement that foreign establishments identify each person who imports or offers for import is not said to be limited to persons known to the establishment (unlike the requirement that they identify “importers”). The preamble to the proposed rule included statements that were inconsistent with the FD&C Act in this regard, suggesting that foreign establishments would be required to report the name of each person

known to the establishment

who imports or offers for import its drug(s) into the United States. See,

e.g.,

71 FR 51276 at 51289. In fact, the proposed rule (proposed § 207.25), the final rule, and the FD&C Act all require foreign establishments to report, when registering, the name of each person who imports or offers for import its drug(s) into the United States without regard to whether such persons are known to the establishment. Therefore, it is important that we define “person who imports or offers for import” in a way that is practical, useful, and consistent with this understanding.

Our intention in defining this term is to include foreign persons who are primarily responsible for sending a drug to the United States. Foreign establishments are reasonably expected to know the identities of such persons. In many cases, the establishment itself will be a person who imports or offers for import its drugs into the United States. In other cases, it will be a person the foreign establishment engages to send one or more drugs to the United States. It will generally be the foreign person who owns the drug and sells or enters into a contractual obligation to supply the drug to a person in the United States.

In light of the comments received and FDA's objectives, the final rule defines “person who imports or offers for import” to mean the owner or exporter of a drug who consigns and ships a drug from a foreign country to the United States. This definition includes persons who send a drug to the United States by international mail or other private delivery service, but does not include carriers who merely transport the drug. This definition is not intended to include persons operating merely as customs brokers.

g. Manufacture, manufacturer.

The definitions of “manufacture” and “manufacturer” in § 207.1 of this final rule include minor editorial revisions for clarity and new references to animal feed bearing or containing a new animal drug.

(Comment 12) Some comments stated that the definition of “manufacturer” should specify that it applies only to entities manufacturing drugs for commercial distribution.

(Response) We disagree with the recommendation that the definition of “manufacturer” be limited to drugs manufactured “for commercial distribution.” The underlying statutory provisions require registration of establishments where drugs are manufactured, without regard to commercial distribution (section 510(c) of the FD&C Act), but require listing of drugs that are manufactured for commercial distribution (section 510(j) of the FD&C Act). Accordingly, under § 207.17 of this final rule, each domestic establishment where a drug is manufactured (or repacked, relabeled, or salvaged) must be registered unless exempt from registration under section 510(g) of the FD&C Act or under § 207.13, regardless of whether the drug is commercially distributed. The drug listing obligation, as described in § 207.41, applies to drugs that are manufactured, repacked, relabeled, or salvaged for commercial distribution. (See separate definition of “commercial distribution.”)

(Comment 13) One comment asked that drug sponsors be included in the definition of manufacturer. Other comments suggested that FDA add “product formulator” to the definition of “manufacturer” or provide definitions for terms such as “drug sponsor.” These comments pointed out that the holder of an approved application, such as an NDA, or the formulator of a nonprescription monograph product may use a contract manufacturer to produce the product for distribution under the name of the application holder or the product formulator. Some comments recommended that the final rule treat such application holders or product formulators as manufacturers so they would register their establishments and list such products and that it exempt contract manufacturers from the drug listing requirement.

(Response) We decline to add the application holder or “product formulator” concepts to the definition of “manufacturer.” Under section 510(c) of the FD&C Act, the obligation to register drug establishments rests on owners or operators of establishments engaged in the manufacture (including repacking, relabeling, and salvaging) of drugs, and the listing obligation applies to “every person who registers.” FDA recognizes that this language could be read broadly to encompass entities that develop or formulate drug products without performing manufacturing operations. However, considering the objectives behind drug registration and listing, we are currently interested in the registration of establishments where manufacturing operations (including repacking, relabeling, and salvaging) take place and the listing of drugs handled at those establishments.

We recognize, however, that an application holder or a product formulator using a contract manufacturer to manufacture a drug may wish to submit drug listing information for that product directly to FDA. Although the actual manufacturer of the drug has the legal obligation to list it, FDA would accept listing information for the drug submitted by its formulator or any other person acting as an authorized agent for the manufacturer. When we use the term “authorized agent” in this final rule, we mean a person who is authorized to act on behalf of another. The term “authorized agent” should not be confused with the United States agent referred to in § 207.69(b).

(Comment 14) Several comments asked for clarification on how the terms “manufacture,” “repackage,” “relabel” and “private label distributor” would apply to the medical gas industry and pointed out that certain medical gas operations, such as the transfilling of gas from one container to another, have long been treated as drug manufacturing by FDA but, under the proposed rule, would seem to qualify as “repacking.” These comments asked FDA to classify medical gas refillers as “manufacturers” rather than “repackers” in the final rule.

(Response) FDA agrees that these important points require clarification. Nothing in this final rule is intended to alter the definitions applicable to FDA's regulations governing current good manufacturing practices for drug products, parts 210 and 211. Therefore, the definition of “manufacture, processing, packing, or holding of a drug product” currently appearing in § 210.3(b)(12) will continue to apply to medical gases as that definition has always applied.

For purposes of part 207, we will interpret the definition of “manufacture” in § 207.1 as including the initial manufacturing process that produces or purifies a medical gas, whether by air separation, chemical reaction, or other process. Additionally, the mixing of two or more medical gases to produce a combination would also qualify as “manufacture” under § 207.1. The impact of this interpretation is that a person who thus qualifies as a manufacturer of a medical gas will be required to submit the drug listing information required under § 207.49 of this final rule (“What listing information must a registrant submit for a drug it manufactures?”) in addition to registering the establishment(s) at which manufacturing is conducted.

All subsequent transfillings of a medical gas from one container to another (

i.e.,

from tanker trucks into standing tanks and from standing tanks into smaller containers, etc.) would fall within the definition of “repack or repackage” in § 207.1 of this final rule. The impact of this interpretation is that a person who thus qualifies as a repacker of a medical gas will be required to submit the drug listing information required under § 207.53 of this final rule (“What information must a registrant submit for a drug that it repacks or relabels?”) in addition to registering the establishment(s) at which repackaging is conducted. Comments opposing this classification expressed concern that under the proposed rule, repackers would be required to identify the NDC assigned to a drug immediately before it is received by the repacker as information that must be submitted to obtain an NDC for a repackaged drug

under proposed § 207.33(d)(1)(ii). See our response to Comment 73 regarding an exemption for medical gases from the requirement that registrants submit such source NDCs for drugs they repackage or relabel.

The definition of “relabel” in § 207.1 of this final rule applies to medical gases. It refers to changing or altering the existing label on a drug or drug package, without repacking the drug or drug package. A person who places a label on a repackaged drug (

e.g.,

a medical gas recently filled into a canister) for the first time qualifies as a “repackager” as that term is defined in this final rule.

The term “private label distributor” is defined in § 207.1 of this final rule to mean, with respect to a particular drug, a person who did not manufacture, repack, relabel, or salvage the drug but under whose label or trade name the drug is commercially distributed. This definition applies equally to private label distributors of medical gases and other drugs. A medical gas transfiller is a repackager, and not a private label distributor, under this final rule. As discussed in our response to comment 16, private label distributors do not—by reason of their status as private label distributors—have an obligation to register establishments or list drugs. They must have labeler codes, obtained under new § 207.33(c), and they may submit drug listing information or establishment registration information if acting as the authorized agent of a registrant on whose behalf the information is submitted.

h. Material change.

In the proposed rule, “material change” was defined as any change in any drug listing information, excluding labeling changes in arrangement or printing or labeling changes of an editorial nature. This definition is retained in the final rule with minor revisions to clarify that material change also does not include changes in the format of labeling, or the inclusion of a bar code or the initial inclusion of an NDC on a label.

(Comment 15) One comment asked FDA to clarify the types of labeling changes that would qualify as a material change and, hence, require reporting as an update to drug listing information under § 207.57. This comment specifically suggested examples of labeling changes that would qualify as significant changes in the labeling of a prescription drug product or significant changes in the label or package insert of an OTC drug product.

(Response) In referring to “significant” labeling changes, this comment seems to relate to the longstanding definition of “material change” in § 207.3(a)(3), prior to this final rule, which encompassed labeling changes described as “significant.” Today's final rule revises that definition so that material change includes any labeling change other than changes in the format of labeling, changes of an editorial nature, inclusion of a bar code, or initial inclusion of an NDC. In this context, changes of an editorial nature would not include any changes that add or revise meaning.

Thus, the new definition of “material change” adopted as part of this final rule is broader than the previous definition and is not limited to “significant” changes. The definition includes—with very few exceptions—any change in previously reported drug listing information. FDA intends to rely primarily on new § 207.57 to maintain an up-to-date database of current drug labeling. Registrants should submit current labeling (and a resubmission of all listing information) each time they submit a drug listing update to report changed information under § 207.57.

i. Private label distributor.

We proposed to define “private label distributor” to mean a person who owns or operates an establishment that commercially distributes, under its own label or trade name, any drug manufactured, repacked, relabeled, or salvaged by a registered establishment. In the preamble to the proposed rule we explained that the private label distributor does not engage in any activities performed by a manufacturer, repacker, relabeler, or salvager for the drug it distributes (71 FR 51276 at 51290).

In the final rule, private label distributor is defined to mean, with respect to a particular drug, a person who did not manufacture, repack, relabel, or salvage the drug but under whose label or trade name the drug is commercially distributed. We have also defined “private label distribution” in this final rule to mean commercial distribution of a drug under the label or trade name of a person who did not manufacture, repack, relabel, or salvage that drug.

(Comment 16) Some comments requested clarification regarding the distinction between private label distributors, manufacturers, and wholesale distributors. Others urged FDA to allow private label distributors to list the drugs they distribute. One comment requested clarification regarding the responsibilities of private label distributors under part 207.

(Response) We agree that more clarity is needed regarding these terms and the registration and listing obligations associated with private label distribution of drug products. We have eliminated the mention of establishment ownership in the proposed rule's definition of “private label distributor” because private label distributors do not necessarily own establishments that require registration under section 510 of the FD&C Act. We have also clarified that an entity may act as a private label distributor with respect to a particular drug. For example, if a drug manufacturer distributes, under its own name or trade name, a drug manufactured entirely by a contract manufacturer, it is acting as a private label distributor with respect to that drug. The difference between private label distributors and wholesale distributors or others involved in drug distribution is that a private label distributor's name, trade name, or label appears on the product. A common example of private label distribution is the sale of aspirin under a retail pharmacy's brand name when the retail pharmacy did not manufacture the product. As defined in this final rule, private label distribution encompasses the use of any brand name or business name on a drug product where the named business or the owner of the brand name did not manufacture the drug. Thus, as we are defining the term in part 207, a private label distributor may, but does not necessarily, operate retail stores or play a role in the physical distribution of the drug product. Even without using a brand name, if an entity is identified as the distributor or marketer of a drug under § 201.1 of the drug labeling regulations, without having manufactured the drug, that person will qualify as a private label distributor as the term is defined in this final rule.

Under this final rule, private label distributors do not have registration or listing obligations with respect to drugs for which they merely act as private label distributors. Only manufacturers, repackers, relabelers, and salvagers have an obligation to register and list. Private label distributors are subject to this final rule only in that they must apply for an NDC labeler code as described in § 207.33(c) and update the information submitted under that section when the information changes. Private label distributors are in the best position to obtain their own labeler codes and update information associated with those codes, thereby preventing potential submissions of inconsistent or inaccurate information by multiple contract manufacturers.

A person who is a private label distributor with respect to a particular drug does not for that reason incur an establishment registration or listing

obligation. The FD&C Act and the regulations in part 207 both place the registration and listing obligation on persons who manufacture, repack, relabel, or salvage drugs. The registration and listing obligation thus rests with the actual manufacturer, repacker, relabeler, or salvager whether or not a product is intended for private label distribution. For this reason, the final rule does not include provisions regarding establishment registrations or drug listings submitted by private label distributors.

We recognize, however, that some private label distributors are in a position to supply listing information, including NDCs, for drugs distributed under their names and may prefer to do so. FDA will accept registration and listing information submitted by any authorized agent acting on behalf of a manufacturer, repacker, relabeler, or salvager, and this includes a private label distributor authorized by a manufacturer, repacker, relabeler, or salvager, to submit drug listing information on its behalf. In these cases, the manufacturer, repacker, relabeler, or salvager remains responsible for compliance with all registration and listing requirements and the accuracy of the information submitted by its agent.

A person who acts merely as a wholesale distributor of a drug product (i.e, a person who did not manufacture, repack, relabel, or salvage the drug product and whose name, trade name, or label does not appear on the drug product) does not incur obligations under this rule.

j. Relabel, relabeler, repack, repacker.

We proposed to define “relabel” to mean changing the label or labels on a drug or drug package, or adding to the labeling for a drug or drug package, without repacking the drug or drug package. We also proposed to define “relabeler” to mean a person who owns or operates an establishment that relabels a drug.

We proposed to define “repack” to mean repack or repackage or otherwise change the container or wrapper of a drug or drug package. Similarly, we proposed to define “repacker” to mean a person who owns or operates an establishment that repacks a drug or drug package.

In the final rule, these definitions are clarified and revised in response to comments.

(Comment 17) Some comments noted that the definition of relabel could include wholesale drug distributors who add information to outer container labels for purposes of delivery to a customer, customer identification, inventory management, special handling instructions, or to aid in compliance with Federal and State pedigree requirements. Commenters urged us not to require establishments (

e.g.,

distribution facilities) where such relabeling occurs to register and list.

(Response) We agree generally with these comments and have revised the definition of “relabel” in the final rule to exclude the addition or modification of information affixed solely for purposes of delivery to a customer, customer identification, or inventory management. However, we did not exclude the addition of special handling instructions from the definition of “relabel,” as recommended in these comments. Such an exclusion might be misinterpreted as accommodating revised storage instructions in drug labeling. However, FDA would not object to the addition of storage information to an outer label if such information is not inconsistent in any way with storage instructions appearing elsewhere in the drug's labeling. In that case, FDA would not regard the addition of such storage information to an outer container label as relabeling that would subject a person to registration and listing.

k. Representative sampling of advertisements

and

Representative sampling of any other labeling.

The definitions of these terms included in the proposed rule appear in this final rule with one minor revision.

(Comment 18) The preamble to the proposed rule included a brief discussion of these definitions. That discussion pointed out a confusing aspect of the previous definitions of these terms and the previous definition of the term “advertising and labeling” in part 207. See 71 FR 51276 at 51291. One comment argued that there was no conflict in these definitions and urged FDA to retain our previous definitions of “representative sampling of advertisements” and “representative sampling of any other labeling.” This comment pointed out that the examples given in those previous definitions were helpful.

(Response) We disagree with this comment. The revised definitions are intended to eliminate some confusion associated with the previous definitions as explained in the preamble to the proposed rule. The examples appearing in the previous definitions read as follows: “If more than one medical journal advertisement is used but the promotional content is essentially identical, only one need be submitted” and “if more than one brochure is used but the promotional content is essentially identical, only one need be submitted.” The quoted language served as common sense guidance regarding the application of the definitions without being a central part of the definitions. Although omitting that language from the definitions included in the proposed rule and this final rule, FDA is not disavowing the examples or suggesting that registrants should take a different approach.

2. Who does this part cover? (§ 207.9)

The Agency proposed new § 207.9 to clarify the types of businesses that are subject to drug establishment registration and listing under part 207. Section 207.9 is retained in this final rule with certain revisions and clarifications.

Section 207.9(a)(3) of this final rule clarifies that private label distributors are subject to part 207. As discussed previously in this document, private label distributors do not have an obligation to register an establishment or list any drugs arising from their activities as private label distributors. They are, however, expected to obtain NDC labeler codes under § 207.33(c) of this final rule and update the information reported to FDA under § 207.33(c) as required by § 207.33(c)(2).

Section 207.9(a)(4) of this final rule is revised to state more clearly its applicability to establishments engaged in the manufacture, repacking, relabeling, or salvaging of drugs regulated under a BLA. These establishments are subject to part 207 unless they are required to register and list under part 607 (ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS).

Section 207.9(a)(5) of this final rule is revised to state that HCT/Ps, as defined in § 1271.3(d), are subject to registration and listing under part 207 if they are drugs regulated under section 505 of the FD&C Act or under section 351 of the PHS Act. A conforming amendment is made to § 1271.1. Manufacturers of HCT/Ps that are regulated under section 361 of the PHS Act (42 U.S.C. 264) and not under section 351 will remain subject to registration and listing under part 1271.

(Comment 19) Comments requested clarification on the applicability of this rule to contract manufacturers and private label distributors of drug products, saying it was not clear in the proposed rule how contract manufacturers are to handle establishment registration and labeler code assignment.

(Response) Manufacturers of drug products are obligated by the FD&C Act and by this final rule—whether or not

they are contract manufacturers—to register their establishments and list the drugs they manufacture for commercial distribution (as the term “commercial distribution” is defined in new § 207.1). Sections 207.49 and 207.53 of this final rule require manufacturers, repackers, and relabelers to provide their own NDC (an NDC that includes the registrant's own labeler code) for each drug they list. (Salvagers are not required to provide new NDCs when listing drugs they salvage because a drug's NDC does not change when it is merely salvaged, and not repacked or relabeled. A person who salvages and then repacks or relabels a drug is a repacker or relabeler, as those terms are defined in § 207.1, and must register and list as a repacker or relabeler.) This provision requires manufacturers, repackers, and relabelers responsible for listing drugs, including contract manufacturers, to obtain an NDC labeler code in accordance with new § 207.33(c).

When listing a human drug manufactured for private label distribution (distribution under the name or trade name of someone other than the drug's manufacturer, as defined in new § 207.1), §§ 207.49 and 207.53 require registrants to provide two NDCs, one that includes the registrant's own NDC labeler code and one that includes the NDC labeler code of the private label distributor. As stated in response to comment 16, FDA will accept drug listing information submitted by a private label distributor (or anyone else) if properly authorized to act as an agent for the actual manufacturer. The use of an agent to handle establishment registration or drug listing submissions does not, however, transfer legal responsibility for complying with this final rule from a manufacturer, repacker, relabeler, or salvager to its agent. Animal drugs manufactured for private label distribution should be listed under a single NDC that includes the labeler code of the private label distributor.

Note that the term “private label distributor” is defined in new § 207.1 to mean, with respect to a particular drug, a person who did not manufacture, repack, relabel, or salvage the drug but under whose label or trade name the drug is commercially distributed. FDA's statements in this document that private label distributors are not obligated to register their establishments or list the drugs they distribute are premised on this definition. If someone who would otherwise qualify as a private label distributor carries out testing or control procedures applied to the final product,

e.g.,

systematic batch release testing required under current good manufacturing practices, that person may qualify as a manufacturer (see the definition of “manufacture” in new § 207.1) and need to register its establishment where the testing or control procedures are carried out. (But if a private label distributor uses a contract laboratory to carry out the testing or control procedures, the contract laboratory, not the private label distributor, may qualify as a manufacturer and need to register its establishment.) Likewise, if someone qualifies as a private label distributor with respect to one or more drugs, but also qualifies as a manufacturer, repacker, or relabeler with respect to other drugs, that person would need to register the establishment where manufacturing, repacking, or relabeling is conducted and list the drugs that are manufactured, repacked, or relabeled for commercial distribution at the registered establishment.

Entities that qualify as private label distributors under this final rule and do not also manufacture, repack, relabel, or salvage any drugs may already have effective establishment registrations and drug listings submitted in the past. We do not expect these entities to renew their registrations after the effective date of this final rule. They may either cancel their registrations or allow their registrations to lapse by not making any further submissions. Any drug listings submitted in the past by entities that qualify as private label distributors under this final rule for drugs they do not manufacture, repack, relabel, or salvage should be transferred to the actual manufacturers, repackers, relabelers, or salvagers of the listed drugs.

(Comment 20) One comment asked FDA to clarify whether radiologic products are subject to this rule.

(Response) This comment did not elaborate on the types of products encompassed by the question so we are unable to respond specifically. There is not an exemption from the establishment registration and drug listing requirements for manufacturers of radioactive drugs, also known as radiopharmaceutical products. Anyone with questions about the applicability of part 207, either before or after this final rule, to radioactive drug products should contact the electronic Drug Registration and Listing System staff in the Office of Compliance at FDA's Center for Drug Evaluation and Research (CDER). For diagnostic device products that include a radioactive drug constituent part, see our response to comment 22 in this document regarding drug/device combination products. Also see part 807 regarding establishment registration and listing for radiologic device products. Positron emission tomography (PET) drugs are subject to part 207, as stated in § 207.13(l)(1) and as discussed in the proposed rule (71 FR 51276 at 51285).

(Comment 21) One comment requested guidance regarding the information needed for “active drug substance manufacturers” to register and list.

(Response) In this final rule, the term “active pharmaceutical ingredient” (API) is defined in § 207.1. The registration obligation applies to each domestic establishment that manufacturers, repacks, relabels, or salvages a drug or an animal feed bearing or containing a new animal drug (whether or not that product is commercially distributed). It also applies to each foreign establishment that manufacturers, repacks, relabels, or salvages a drug or an animal feed bearing or containing a new animal drug that is imported or offered for import into the United States. In each case, the term “drug” includes: (1) An API by itself, (2) an API that has been combined with one or more other APIs or inactive ingredients (see definition of “unfinished drug” in § 207.1), and (3) finished drug products (see definition of “finished drug product” in § 207.1).

The information that must be submitted for establishment registration is set forth in new § 207.25. These information elements do not differ depending on whether the registrant handles APIs, other unfinished drugs, or finished drugs.

The information that must be submitted with a drug listing is set forth in new § 207.49 for a drug the registrant manufactures, § 207.53 for a drug the registrant repacks or relabels, and in § 207.54 for a drug the registrant salvages. As specified in § 207.41, the drug listing obligation applies only to drugs that are manufactured, repacked, relabeled, or salvaged for commercial distribution. Sections 207.49, 207.53, and 207.54 indicate some minor differences in the information that must be submitted depending on whether the drug is finished or unfinished. For example, § 207.49(a)(15)(iv) describes the labeling that must be submitted for an unfinished drug.

(Comment 22) One comment asked, in the context of the proposed rule's requirement that NDCs appear on drug labels, how the rule would apply to drug/device combination products. Other comments asked how registration and listing should be handled for drug/device combination product kits. (See the definition of “combination product” in § 3.2(e) (21 CFR 3.2(e)), unaffected by this rulemaking.)

(Response) We acknowledge that the proposed rule did not include an explanation of its applicability to drug/device combination products, including how manufacturers of such products should register their establishments, list their combination products, and provide related information on the labels of their combination products. The codified of this final rule likewise does not contain specific provisions regarding drug/device combination products. FDA expects to further address drug/device combination product registration and listing in the future. As stated previously in this document, we also are not finalizing the proposed amendment to § 201.2 that would have required human-readable NDCs on the labels of all drugs subject to the listing requirement.

3. Who is exempt from registration and listing requirements? (§ 207.13)

The proposed rule included a new § 207.13 aimed at clarifying the types of businesses that are exempt from drug establishment registration and listing under part 207. Section 207.13 is retained in this final rule with certain revisions and clarifications. Some exemptions described in § 207.13 are derived directly from section 510(g) of the FD&C Act. Other exemptions are established under section 510(g)(5) of the FD&C Act supported by our finding that registration by such classes of persons is not necessary for the protection of the public health.

(Comment 23) Several comments argued against the elimination of two existing exemptions from registration and listing that the proposed rule would have revoked. These two exemptions encompass: (1) Drugs imported under section 801(d)(3) of the FD&C Act (often referred to as “import for export”) and (2) drugs that enter a foreign trade zone and are re-exported from that foreign trade zone without having entered U.S. commerce.

(Response) Previous § 207.40(b) stated that no drug may be imported or offered for import into the United States unless the drug is listed and manufactured, prepared, propagated, compounded, or processed at a registered foreign establishment. The section also stated that this prohibition did not apply to, among other things, components of drugs imported under section 801(d)(3) of the FD&C Act. Section 801(d)(3) allows persons to import certain articles, including components of drugs, if specified conditions are met, provided that the imported articles are further processed or incorporated into products and exported or, if not used, the imported articles are destroyed or exported. Thus, previous § 207.40(b) exempted certain foreign establishments from the establishment registration and listing requirement.

Previous § 207.40(a) stated that a foreign establishment was not required to comply with the registration and listing requirements if its drug entered a foreign trade zone and was re-exported from that foreign trade zone without having entered U.S. commerce.

Upon careful consideration of the comments received, we have decided to retain both exemptions in this final rule. Therefore, under § 207.13(j) of this final rule, if all the conditions of section 801(d)(3) of the FD&C Act are satisfied, a component of a drug will not be excluded from importation into the United States by reason that it is unlisted or was manufactured at an unregistered foreign establishment. Additionally, under § 207.13(j) of this final rule, a foreign establishment does not incur a registration and listing obligation if its drug enters a foreign trade zone and is re-exported from that foreign trade zone without having entered U.S. commerce. These exemptions pertain only to drugs that are re-exported or components of drugs that are processed or incorporated into products and then exported, and these exemptions pertain only to foreign establishments. If an establishment located within a foreign trade zone manufactures, repacks, relabels, or salvages a drug for commercial distribution in the United States, that establishment would need to register and list those drugs it handles for U.S. commercial distribution. Additionally, if a foreign establishment exports drugs to the United States relying on either of these exemptions, but also exports other drugs for commercial distribution in the United States, it must comply with the registration and listing requirements for those drugs that are commercially distributed in the United States.

The corresponding exemptions for blood product establishments are also retained in § 607.40 under this final rule.

(Comment 24) One comment asked FDA to confirm that animal biological products are not subject to this rule.

(Response) Some biological drugs intended for administration to animals are regulated by the U.S. Department of Agriculture (USDA) under the Virus, Serum, and Toxins Act of 1913. Section 510.4 (21 CFR 510.4) states that animal drugs produced and distributed in full conformance with the Virus, Serum, and Toxins Act and any regulations issued thereunder shall not be deemed to be subject to section 512 of the FD&C Act (includes premarket approval and other requirements for new animal drugs regulated by FDA). As proposed in § 207.13(g), the final rule includes an exemption applicable to these products in § 207.13(h).

(Comment 25) Comments from the medical gas industry expressed concern about the ability of entities such as pharmacies, hospitals, clinics, and emergency responders to refill medical gas cylinders if the repackaging would require the repacker's NDC to appear on the label of the repackaged product. The comment stated that if these entities are exempt from part 207, they cannot obtain an NDC.

(Response) Our decision not to include the proposed amendments to § 201.2 that would have required human-readable NDCs on drug labels renders the concern expressed in this comment moot. We would like to confirm that pharmacies, hospitals, clinics, other health care entities, and public health agencies that qualify as exempt from the registration and listing requirements under § 207.13 of this final rule do not lose their exemptions by dispensing medical gases or filling medical gas containers in the normal course of their activities.

C. Registration (Part 207, Subpart B)

1. Who must register? (§ 207.17)

Section 207.17 describes who is required to register an establishment under part 207. This section is reworded in the final rule: (1) To distinguish between domestic and foreign manufacturers, repackers, relabelers, and salvagers and (2) to clarify that FDA will accept registration information submitted by a private label distributor only if it is acting as an authorized agent for and submitting information pertaining to an entity that has an establishment registration obligation.

(Comment 26) One comment asked FDA to clarify whether a storage facility that does not repack or relabel drugs is required to register under part 207.

(Response) A facility at which drugs are stored, such as a warehouse, does not need to be registered provided drugs are not manufactured, repacked, relabeled, or salvaged (as those terms are defined in § 207.1) at the facility. Note that the definition of “manufacture” includes sampling, testing, or control procedures applied to the final product or to any part of the process. Thus, for example, if a warehouse includes a temperature-controlled storage area where drug samples are stored for stability testing to satisfy current good manufacturing practice requirements, that activity would qualify as a manufacturing

operation and require registration of the warehouse as a drug establishment. Other State or Federal requirements may apply to such facilities.

As explained in response to Comment 17, we have revised the definitions of “relabel” and “relabeler” so they do not include the addition or modification of information affixed to drug packaging solely for purposes of delivery to a customer, customer identification, or inventory management. Therefore, the addition or modification of such information at a warehouse does not trigger the need to register it as an establishment.

2. When must initial registration information be provided? (§ 207.21)

Proposed § 207.21 described when initial registration information must be submitted for an establishment newly required to register under part 207. The provision is retained in this final rule and reorganized into paragraphs (a) and (b) for improved clarity.

(Comment 27) One comment suggested that the words “for commercial distribution” be added to § 207.21, suggesting that establishment registration is required only for establishments at which drugs intended for commercial distribution are manufactured, repacked, relabeled, or salvaged.

(Response) The absence of these words—“for commercial distribution”—from § 207.21 is intentional and comports with section 510 of the FD&C Act. Any establishment at which drugs are manufactured, repacked, relabeled, or salvaged must be registered under part 207, unless exempt from registration under section 510(g) of the FD&C Act or under the relevant regulations (§§ 207.13, 607.65, or 1271.15, as applicable) whether or not the drugs are commercially distributed. Accordingly, an establishment at which an investigational drug is manufactured is subject to the establishment registration requirement. The listing obligation, on the other hand, applies to drugs that are for commercial distribution.

3. What information is required for registration? (§ 207.25)

Proposed § 207.25 described the information that must be submitted to register an establishment. The provision is retained in the final rule with minor substantive and editorial revisions. Substantively, new § 207.25 no longer requires the submission of fax numbers to register establishments and now includes the new statutory requirement that registrants provide a UFI for each establishment. (See our discussion of establishment registration numbers and UFIs in section II.B, Changes to the Proposed Rule.) New § 207.25 also clarifies that the physical address of each establishment is required (rather than a post office box, for example), and a mailing address is required for the establishment's official contact.

(Comment 28) One comment asked FDA to clarify what format should be used when a foreign establishment submits contact information for each importer. This comment also asked FDA to explain who should submit establishment registration information when a business has both foreign and U.S. establishments.

(Response) According to new § 207.61, all information transmitted to FDA under part 207, including establishment registration information, must be transmitted to FDA in electronic format unless a waiver is granted. FDA's systems for electronic registration include fields for information elements such as the required contact information for U.S. importers of drugs manufactured, repacked, relabeled, or salvaged at a foreign establishment.

Section 207.17 addresses this comment's second question, who should submit establishment registration information when a business has both foreign and U.S. establishments? This section states that when operations are conducted at more than one establishment, and common ownership and control among all the establishments exists, the parent, subsidiary, or affiliate company may submit registration information for all establishments. This applies whether the establishments are domestic, foreign, or both.

(Comment 29) One comment asked FDA to exempt contract manufacturers from the requirement that establishments identify each importer in the United States of drugs they manufacture, repack, relabel, or salvage that is known to the establishment as well as each person who imports or offers for import such drugs to the United States. This comment stated that contract manufactures may not have this information.

(Response) This requirement is retained in the final rule, in § 207.25(h). The provision implements a statutory requirement (section 510(i)(1) of the FD&C Act). This requirement pertains only to foreign establishments, and it requires them to identify “importers” known to the establishment and “persons who import or offer for import,” as these terms are defined in § 207.1. Both of these definitions have been refined and narrowed in this final rule. A foreign contract manufacturer exporting drugs to the United States should be able to identify such persons.

4. What are the requirements for reviewing and updating registration information? (§ 207.29)

Section 207.29 describes the requirements for: (1) Expedited updating of certain changes to establishment registration information and (2) annual reviewing and updating of establishment registration. This section is retained in the final rule with very minor revisions. Fax numbers are no longer mentioned in § 207.29(a) because they are no longer required for establishment registration. Additionally, the dates during which the annual review and update of registration information must take place have been adjusted to match section 510(b)(2) of the FD&C Act, added by FDAAA.

(Comment 30) Some comments opposed the requirement that if no changes have occurred since the last registration, registrants certify that no changes have occurred.

(Response) The annual review and updating of establishment registration information is critical to the integrity of FDA's database. The requirement that registrants certify that no changes have occurred when that is true provides important assurance that registrants have reviewed the establishment registration information they previously submitted. Otherwise, FDA would need to interpret silence from a registrant as indicating either that the information remains up to date or that the registrant may have neglected to review and update the information. We further note that section 510(b)(1) of the FD&C Act now requires annual registration of establishments between October 1 and December 31, and the option to certify that no changes have occurred since the last registration is a minimally burdensome implementation of this statutory requirement.

Please see our response to Comment 74, which addresses this issue in the context of drug listing updates.

D. National Drug Code (Part 207, Subpart C)

1. What is the national drug code (NDC), how is it assigned, and what are its requirements? (§ 207.33)

The NDC provisions in this final rule have been revised in response to comments received on the proposed rule. Most significantly, new § 207.33:

• Allows for 11 digits in the NDC (when 10-digit combinations are exhausted).

• Reflects that registrants will propose their own NDCs for drugs they

list. Under the proposed rule, FDA would have assigned NDCs in response to submissions from registrants. Under this final rule, each registrant must propose its own NDC for each drug the registrant lists. FDA will assign the proposed NDCs to the listed drugs unless they are improperly formatted, previously assigned to a listed drug, or reserved.

• Includes new NDC formatting requirements for registrants to observe when proposing NDCs.

• Transfers some information that would have been required under proposed § 207.33(c) (What information must a manufacturer submit before we will assign an NDC number to a drug?) to information that must be included in a drug listing submission.

• Allows certain drug products to be assigned alternatively formatted NDCs if approved by the Center Director. This applies to the HCT/Ps specified in new § 207.33(b)(4) if they are minimally manipulated.

• Includes a new § 207.33(c) that explains who must obtain an NDC labeler code and how labeler codes are assigned and updated.

• Includes new provisions in § 207.33(d) that explain how a proposed NDC can be voluntarily reserved.

Comments on the NDC provisions of the proposed rule and FDA's responses are summarized in this document. This does not include some comments that have been made moot by the revisions summarized previously.

(Comment 31) FDA received many comments opposing the proposed rule's requirement that FDA, rather than registrants, generate and assign the complete NDC for drugs that are subject to listing. Some comments were concerned about possible delays associated with NDC request submissions. Others were concerned about losing control over numbering conventions that individual registrants may apply to their own product codes and package codes. One comment expressed concern that subjecting OTC monograph products to an NDC assignment process could begin to resemble an FDA approval process for such products.

(Response) The objective behind FDA's proposal to generate and assign NDCs was to assure they are assigned appropriately. Although we did not intend FDA's issuance of NDCs to be time consuming or to operate as an approval process, we recognize that FDA's objectives can be met in a way that is more flexible and less burdensome for registrants. Accordingly, the proposed requirement that FDA generate the complete NDC for each listed drug is not included in this final rule.

Under new § 207.33(d), registrants, not FDA, will generate NDCs for assignment to their listed drugs. An NDC is considered to be “proposed for assignment” when a registrant submits it for the first time with drug listing information in accordance with § 207.49 or § 207.53. If the proposed NDC conforms to the formatting requirements of § 207.33, is not reserved for a different drug, and was not previously assigned to a different listed drug, FDA will assign the proposed NDC when it receives all required listing information for the drug.

(Comment 32) Some comments asked how far in advance of marketing a drug for the first time an NDC may be requested. Comments also pointed out that manufacturers need to know the NDC for a drug in development prior to the time of drug listing.

(Response) As explained in response to Comment 31, this final rule requires registrants to propose their own NDCs for drugs they list. FDA will assign a proposed NDC to the drug identified by the registrant if the proposed NDC conforms to the formatting requirements of § 207.33, is not reserved for a different drug, and was not previously assigned to a different listed drug.

We recognize that a mechanism for reserving a specific NDC may be helpful, as this would provide greater certainty that a proposed NDC will be accepted by FDA when it is included with a listing submission at the time of marketing. Accordingly, this final rule includes a new § 207.33(d)(3) that allows a person to voluntarily reserve a proposed NDC for a period of 2 years prior to its inclusion in a drug listing submission for the first time. Note that an NDC reserved under § 207.33(d)(3) would need to include most importantly a labeler code and a product code. At the discretion of the person submitting the reservation request, a single package code could be included, or not, with one or more package codes included later in NDC(s) submitted with complete drug listing information.

Certain minimal information must be submitted to reserve a proposed NDC, as specified in new § 207.33(d)(3). This information does not include identification of the drug's inactive ingredients. Many comments opposed the inclusion of such detailed information in the proposed rule's provision governing NDC requests.

NDCs reserved under § 207.33(d)(3) would be reserved for 2 years unless the person whose labeler code is included in the NDC asks FDA to cancel the reservation earlier. If a reserved NDC is not used during the 2-year reservation period (

i.e.,

is not submitted to FDA with complete listing information for the drug matching the reservation), the NDC will be available for assignment to another drug. Anyone wishing to extend an NDC reservation beyond 2 years may submit another reservation request.

In addition to the procedure established under § 207.33(d)(3), a registrant wishing to reserve an NDC also has the option of submitting complete listing information for a drug that is under development and specifying a future “start marketing date” in the listing submission. That listing submission could then be updated, as needed, when the actual marketing date arrives.

(Comment 33) One comment questioned how, when listing a drug for the first time, a registrant can supply a drug's labeling if the labeling must include the drug's NDC, and if the NDC is not assigned until the drug is listed.

(Response) As explained in response to Comment 1, unlike the proposed rule, this final rule does not require NDCs to appear in human-readable form on drug labels (but an intervening statutory amendment, the DSCSA, does require NDCs to appear as part of the product identifier on certain drug labels). After the effective date of this final rule, our regulations will continue to encourage, but not require, the appearance of human-readable NDCs on drug labels (§ 201.2) and continue to require that NDCs appear in bar codes on drug labels (§ 201.25(c)).

Under this final rule, unlike the proposed rule, registrants are able to develop and propose their own NDCs to FDA. Upon receipt of a first-time listing submission, FDA will assign the NDC proposed by the registrant to the drug being listed unless the NDC is improperly formatted, reserved for a different drug, or was previously assigned to a different listed drug. Registrants are also able to reserve an NDC for a drug under development under § 207.33(d)(3) of this final rule. Accordingly, registrants should not have difficulty determining, with adequate certainty, the NDC for a drug under development.

(Comment 34) Some comments supported the proposed rule's revocation of then-current § 207.35(b)(4)(ii), which stated that the product code of a discontinued product could be reassigned to another product 5 years after the expiration date of the discontinued product or, if there is no expiration date, 5 years after the last shipment of the discontinued product. Commenters generally agreed that the reuse of old NDCs for a different

product in the future can be confusing. One comment, however, urged FDA to allow for the reuse of NDCs.

(Response) FDA is retaining this general prohibition against the reuse of NDCs in the final rule. As indicated in new § 207.33(d)(2), an NDC will not be assigned to a drug if it was previously assigned to a different drug. The prohibition against reuse of NDCs applies to listings submitted on or after the effective date of this final rule. Drugs that are currently listed under NDCs that have been reused in accordance with previous § 207.35(b)(4)(ii) may continue to be listed under such NDCs.

Conversely, if a registrant reintroduces a drug it listed and discontinued in the past, that registrant must list the drug using the same NDC under which it was listed in the past. See § 207.37(b) of this final rule. However, if the reintroduced drug includes changes, compared to the discontinued drug, that would warrant a new NDC under new § 207.35, then it should be listed under a new NDC.

As discussed in response to Comment 19, under new § 207.49, if a private label distributor uses a contract manufacturer to produce a human drug, the contract manufacturer has an obligation to list the drug under two NDCs, one that includes the labeler code of the contract manufacturer and one that includes the labeler code of the private label distributor. If the private label distributor switches to a new contract manufacturer in the future, that new contract manufacturer would also have an obligation to list the drug under two NDCs, one that includes its own labeler code and one that includes the labeler code of the private label distributor. The NDC that includes the new contract manufacturer's labeler code will obviously differ from the NDC under which the previous contract manufacturer listed the drug (because the labeler codes will differ). The NDC that includes the private label distributor's labeler code may be the same as that under which the previous contract manufacturer listed the drug provided: (1) There have been no changes to the drug that warrant a new NDC under § 207.35 and (2) the previous contract manufacturer updates its listing information to indicate it no longer manufactures the drug (as it is required to do under § 207.57 at the time of its next June or December listing update, or sooner at its discretion). If those two conditions do not exist, FDA would accept a listing from the new contract manufacturer under a new NDC that includes the private label distributor's labeler code.

(Comment 35) We received several comments concerning the format of the NDC. Many comments expressed concern about the impact of any changes in the NDC format on various systems that track and use NDCs. Some comments urged FDA to retain the 10-digit NDC format. Others encouraged the adoption of a standard 11-digit NDC. Some comments opposed the possible introduction of alphanumeric NDCs, preferring all numeric NDCs. Others were concerned about the possible coexistence of 10- and 11-digit NDCs.

(Response) FDA is sensitive to these concerns. Section 207.33(b) of this final rule specifies the format of an NDC recognized by FDA. The final rule necessarily includes more specifications than did the proposed rule concerning NDC formatting because under the final rule, registrants, not FDA, develop their own proposed NDCs, and they must all meet certain formatting parameters. The final rule states, for example, that the NDC is 10 or 11 digits to preclude the submission of longer NDCs.

Our regulations have long stated that FDA will expand the labeler code from five to six numeric characters when the available five-character code combinations are exhausted (previous § 207.35(b)(2)(i)). This occurrence is mathematically inevitable and is reflected in new § 207.33(b)(1), which states that the NDC must consist of 10 or 11 digits. FDA will begin issuing 6-digit labeler codes, leading to 11-digit NDCs, only when the available 5-digit labeler codes are exhausted. FDA will not assign 11-digit NDCs until we begin to issue 6-digit labeler codes.

FDA recognizes the desirability of a single, standard format for NDCs, having three segments of consistent lengths, as we eventually transition to six-digit labeler codes. We intend to initiate a public discussion of future formatting options in the near future. In the meantime, the provisions included in this final rule are intended to accommodate the range of existing NDC formats, leaving room for necessary expansion to 11 digits.

This final rule refers to the NDC as a numeric code, not an alphanumeric code. This takes into account comments that objected to the inclusion of alpha characters in NDCs as disruptive of current systems and practices.

(Comment 36) Some comments urged FDA not to require NDCs for HCT/Ps, citing the International Society of Blood Transfusion (ISBT) number as a better means of identifying these products.

(Response) In response to these comments, § 207.33(b)(4) of this final rule states that an alternatively formatted NDC may be used for certain identified HCT/Ps if they are minimally manipulated and if the alternatively formatted NDC is approved by the Center Director (CDER or CBER, as appropriate). Such approval may be indicated in Guidance for Industry issued by one or both Centers or in this preamble, for example. Accordingly, FDA identifies ISBT-128 as a currently approved alternatively formatted NDC to identify HCT/Ps within the scope of § 207.33(b)(4). ISBT-128 is an international standard for the identification of medical products of human origin. Please note that an alternatively formatted NDC approved under § 207.33(b)(4) qualifies as an NDC. HCT/Ps that are not within the scope of § 207.33(b)(4) require traditionally formatted NDCs.

(Comment 37) One comment encouraged FDA to allow a single NDC, with a single package code, to be assigned to an API, which may be commercially distributed in various quantities.

(Response) This comment refers to APIs, but the question applies to any bulk product supplied in variable quantities. We would like to accept non-numeric characters, such as one or more asterisks, in the package code segment of an NDC to indicate a bulk product supplied in various quantities (as was previously done in paper submissions). However, the SPL format, currently specified in the electronic registration and listing guidance, does not accommodate non-numeric characters. Manufacturers in this situation may adopt a variety of practices. They may submit multiple NDCs with package codes corresponding to a variety of commonly ordered package sizes. They may submit an NDC package code corresponding to 1 kilogram (kg), for example, and then treat a shipment of 10 kg as being comprised of 10 units. In some cases, they may submit an NDC with a package code corresponding to a 55-gallon drum, for example, and use that packaging to ship 55-gallon orders as well as orders that are slightly less than 55 gallons in volume.

(Comment 38) One comment recommended that the NDC for a drug that was repacked or relabeled include the product code of the source drug.

(Response) Section 207.53 of this final rule requires repackers and relabelers to list drugs they repack or relabel and requires them to submit an appropriate NDC for each such drug that includes the repacker's/relabeler's labeler code. It would not be feasible to require the NDC for a repacked or relabled drug to include the labeler code of the repacker or relabeler combined with the product code of the source drug. Such a

requirement might produce an NDC that was previously assigned to a different drug. Because registrants will continue to propose their own NDCs under this final rule, a repacker or relabeler may generally adopt the convention proposed in the comment, but may not list a drug under an NDC that was previously assigned to a different listed drug.

Listing submissions for repacked or relabeled drugs must also include the complete NDC assigned to each finished drug received by the registrant for repacking or relabeling (

i.e.,

the source drug), so this link will exist in the drug's listing information.

(Comment 39) Two comments asked whether FDA will assign NDCs to products that do not have application numbers,

i.e.,

products that are not the subject of an approved application.

(Response) This question was posed in the context of the proposed requirement that registrants request an NDC from FDA by submitting information specified in proposed § 207.33(c) prior to a listing submission. In the case of finished drugs, proposed § 207.33(c) would have allowed registrants to submit an approved U.S. application number in place of certain information. As discussed in response to Comment 31, this final rule allows registrants to propose their own NDCs with listing submissions, and FDA will accept those proposed NDCs unless they are formatted incorrectly, reserved for a different drug, or previously assigned to a different drug. Under this final rule, NDCs are still “assigned” only by FDA, after all required listing information is received. We affirm that NDCs will be assigned in this manner to all drugs subject to the listing requirement, including drugs that do not have application numbers. As we have stated in the past (

e.g.,

previous § 207.39 and in the preamble to the proposed rule (71 FR 51276 at 51305)), FDA's assignment of an NDC does not in any way denote FDA approval of a product. Section 207.37 of this final rule states that a product may be deemed misbranded if an NDC is used to denote or imply FDA approval.

(Comment 40) Some comments asked how NDCs will be assigned to multidrug kits. Here we are addressing kits that do not contain medical devices. (See related discussion of drug/device combination products in response to Comment 22.)

(Response) If a product contains more than one finished drug product, co-packaged as a kit, and that kit is commercially distributed, the kit itself must be listed in accordance with § 207.41, under § 207.49 or § 207.53, as appropriate. A registrant submitting the listing should propose an NDC for the kit itself, distinct from any NDCs assigned to individual drug constituents contained in the kit. The NDC proposed for the kit should include the labeler code of the registrant obligated to submit the listing. If the kit is packaged for private label distribution, it should be listed under an additional NDC that includes the labeler code of the private label distributor.

(Comment 41) A comment asked whether a finished drug product, manufactured under one approved application at two different manufacturing sites under the same ownership and control could be listed under a single NDC. In this example, the finished product from each manufacturing site would have the same composition and physical appearance. The comment also asked whether the answer would change if the manufacturing sites are located in two different countries.

(Response) Each manufacturing site would need its own establishment registration under § 207.17 unless exempt under section 510(g) of the FD&C Act or under § 207.13. (Foreign establishments must register only if they manufacture, repack, relabel, or salvage drugs that are imported or offered for import into the United States.) With respect to the drug listing requirement, the proposed rule and the final rule specify in § 207.41(a) that when operations are conducted at more than one establishment, and common ownership and control exists among all the establishments, the parent, subsidiary, or affiliate company may submit listing information for any drug manufactured, repacked, relabeled, or salvaged at any such establishment. This language allows a registrant that manufactures a drug at more than one of its own establishments to submit a single listing for that product, while identifying all establishments where the registrant manufactures the drug under § 207.49(a)(12). The listed drug would have a single NDC in this scenario. The answer does not change if one or more manufacturing sites are located outside the United States.

Note, however, that FDA would also accept multiple listings if a manufacturer in this situation wished for any reason to submit separate listings and NDCs for the same drug manufactured at multiple establishments.

This analysis does not apply to an entity that uses one or more contract manufacturers to manufacture, repack, relabel, or salvage a drug. In that case, each contract manufacturing site must be registered under § 207.17, unless exempt under section 510(g) of the FD&C Act or under § 207.13. If more than one contract manufacturing site is used, and those sites are under common ownership and control, the contract manufacturer could submit a single listing for this drug covering its activities at multiple sites (also listing other drugs it is required to list under § 207.49 or § 207.53). Furthermore, as discussed in our response to comment 19, contract manufacturers must generally list a drug under two NDCs, one that includes the contract manufacturer's labeler code and one that includes the private label distributor's labeler code. In this scenario, a single NDC that includes the private label distributor's labeler code could be used with a drug manufactured at multiple contractor sites along with a single NDC that includes the contract manufacturer's labeler code, provided there are no differences in the product produced at the various sites that would warrant a new NDC under § 207.35.

(Comment 42) One comment asked how registrants should assess whether their existing NDCs comply with this rule. Some comments noted a statement in the preamble to the proposed rule that FDA intends to validate that current NDCs comply with the new regulations when the rule is finalized (71 FR 51276 at 51280) and requested more information about this process.

(Response) This final rule is not intended to require extensive changes to NDCs themselves. The NDC formatting provisions of new § 207.33(b) are intended to accommodate NDC formats currently in use. The 10-digit NDC formats provided for under § 207.33(b) of this final rule include (in terms of numbers of digits in the labeler code, product code, and package code respectively) 4-4-2, 5-3-2, and 5-4-1. Any NDC in one of those formats that is not assigned to multiple drug products and is not assigned to a non-drug product should comply with this final rule. When five-digit labeler codes are exhausted, FDA will begin issuing six-digit labeler codes, allowing for additional formats of 6-3-2 and 6-4-1.

(Comment 43) Some comments encouraged FDA to permit one registrant or business to maintain more than one labeler code. These comments pointed out that mergers and acquisitions in the pharmaceutical industry result in corporate entities responsible for drugs listed under multiple NDC labeler codes. Consolidation of such NDCs to a single labeler code would be burdensome and may not be possible in some cases if, for

example, one product code has been used with two different labeler codes.

(Response) FDA agrees with this comment. We encourage registrants and private label distributors to maintain a single labeler code wherever possible. But FDA will not require each registrant and private label distributor to maintain only one labeler code. This flexible approach accommodates mergers and acquisitions. It departs from a statement in the preamble to the proposed rule that only one labeler code would be used for new NDC numbers that FDA would have assigned prospectively for any given manufacturer, repacker, or relabeler (71 FR 51276 at 51299). It also accommodates situations in which any registrant wishes to maintain different labeler codes for different product lines or situations in which a registrant risks exhausting all available labeler code and product code combinations if the registrant operates with a single labeler code. Importantly, new § 207.33(c)(2) requires each person who is assigned a labeler code to update the information required under § 207.33(c)(1). This will allow FDA to reliably associate every labeler code with the person to whom it is assigned and the person's contact information.

Registrants and private label distributors who currently have NDC labeler codes but for whom FDA does not have up-to-date information described in § 207.33(c)(2) on the effective date of this rule are required to update their information. FDA may refuse to accept new drug listings that include an NDC labeler code for which the information required by § 207.33(c)(2) is not current in our system.

(Comment 44) One comment asked FDA to confirm that a business owning many registered establishments may maintain only one labeler code, so that all of its NDCs include a single labeler code.

(Response) FDA prefers that such a business maintain only one labeler code, and that it use this single labeler code when proposing NDCs for drugs it manufactures, repacks, relabels, or salvages at establishments under common ownership and control. However, as explained in our response to Comment 43, FDA will not require any business to maintain only one labeler code.

(Comment 45) One comment interpreted the proposed rule as preventing an entity that does not distribute its own products from maintaining its own labeler code. The comment recommended that such an entity not be required to assume distribution responsibilities to retain its labeler code.

(Response) FDA is not certain whether this comment is concerned with which NDC would have been required to appear on product labels had we finalized the proposed amendments to § 201.2, or more generally concerned with the NDCs under which private label distributor products are listed. Under § 207.33(c) of this final rule, a labeler code must be requested and maintained by any person who engages in manufacturing, repacking, relabeling, or private label distribution of drug products. The term “private label distribution” is defined in § 207.1 of this final rule to mean commercial distribution of a drug under the label or trade name of a person who did not manufacture, repack, relabel, or salvage that drug. A private label distributor does not need to physically engage in drug distribution to qualify as a private label distributor under this definition and maintain a labeler code under § 207.33(c).

(Comment 46) One comment gave an example of two establishments “located in the same geographical location within two cities located five miles apart” and asked whether those establishments would need separate NDC labeler codes and registration numbers.

(Response) Under the final rule's definition of “establishment,” two establishments located 5 miles apart would not qualify as being at “one general physical location” and would therefore require two separate registrations. Each establishment would be associated with its own UFI and establishment registration number. As stated in § 207.17 of this final rule, when operations are conducted at more than one establishment and common ownership and control among all the establishments exists, the parent, subsidiary, or affiliate company may submit registration information for all establishments. Likewise, with respect to drug listing information, § 207.41 states that when operations are conducted at more than one establishment, and common ownership and control exists among all the establishments, the parent, subsidiary, or affiliate company may submit listing information for any drug manufactured, repacked, relabeled, or salvaged at any such establishment. A single labeler code may be used in the NDCs for all drugs proposed by such a parent, subsidiary, or affiliate company.

(Comment 47) A comment asked FDA to confirm that the NDC assignment requirement for APIs applies to all APIs, whether they are supplied by domestic or foreign establishments.

(Response) Any drug, including an API, manufactured at a domestic establishment for commercial distribution in the United States must be listed under § 207.49 unless exempt under § 207.13. As proposed and under this final rule, the registration and listing requirements apply to foreign establishments whose drugs, including APIs, are imported or offered for import into the United States. See §§ 207.13(j), 207.49, and 207.53.

(Comment 48) Some comments urged FDA to exempt allergenic extract products from the NDC requirement or from drug establishment registration and listing generally. These comments argued that the proposed rule would require manufacturers of allergenic extracts to manage a large number of NDCs without obvious benefits.

(Response) Allergenic extracts are used in the diagnosis and treatment of allergies. As such, they are appropriately regulated as drugs under the FD&C Act and FDA's regulations. Section 510 of the FD&C Act authorizes FDA to exempt certain persons from establishment registration (and hence listing) if registration “is not necessary for the protection of the public health.” We decline to make this finding for allergenic extracts. Such an exemption would diminish FDA's ability to inspect establishments at which allergenic extracts are manufactured and track marketed products.

Both before and after this final rule, our regulations in part 207 have required that each listed drug product have an NDC. We understand that this requires manufacturers of allergenic extracts to associate a unique NDC with each product they manufacture for commercial distribution, and this may result in a large number of NDCs. We believe the public health benefits associated with drug registration and listing outweigh the burden this places on manufacturers to manage a large number of NDCs.

(Comment 49) One comment asked whether drug samples are subject to the NDC requirement.

(Response) Under this final rule, registrants must list drugs they manufacture, repack, relabel, or salvage for commercial distribution. The term “commercial distribution” is defined in a way that encompasses free samples. Because any listed drug requires an NDC, drugs packaged for distribution as promotional samples are expected to have NDCs.

(Comment 50) Some comments recommended that pharmacy compounded drugs be eligible for NDC

assignment. These comments noted that hospital pharmacies use the NDC to reduce medication errors.

(Response) Drug products compounded by a licensed pharmacist or a licensed physician in conformance with section 503A of the FD&C Act are generally exempt from drug establishment registration and listing under part 207 before and after this final rule, consistent with the exemptions for pharmacies and practitioners in section 510(g) of the FD&C Act. The DQSA added section 503B to the FD&C Act. Under section 503B, a compounder can register with FDA as an “outsourcing facility.” Because the FD&C Act now establishes a separate registration and drug product reporting process for such outsourcing facilities, this final rule exempts outsourcing facilities from the registration and listing requirements of part 207. (See new § 207.13(k).)

Compounders that meet the conditions for exemption from registration and listing requirements under part 207 may elect to voluntarily register and list their products under part 207 and obtain NDCs.

2. What changes require a new NDC? (§ 207.35)

Section 207.33(f) of the proposed rule identified the types of changes to a drug that require a new NDC. This final rule includes new § 207.35 that states with greater clarity the types of changes to a drug that require a new NDC. Substantively, new § 207.35 is similar to the corresponding requirements in the proposed rule, but the provision does not require a new NDC when changes are made to inactive ingredients or when the Drug Master File number or Veterinary Master File number, if any, assigned to an API changes.

(Comment 51) Some comments were concerned about the types of changes to a drug that would require a new NDC in the proposed rule. In particular, many comments opposed the proposed requirement that changes in a drug's inactive ingredients would necessitate a new NDC.

(Response) This proposed requirement—that a change in a drug's inactive ingredients would necessitate a new NDC—has not been retained in the final rule. Under both the proposed rule and the final rule, any change in information submitted with a drug listing must be reflected in an updated listing under § 207.57. Certain more significant changes also require a new NDC, as specified in new § 207.35. Upon careful consideration, we agree with those comments that stated it would be unreasonably burdensome to require registrants to submit a new NDC each time they change the inactive ingredient composition of a product.

Some comments questioned the scope of the proposed requirement: Would it apply to changes from one inactive ingredient supplier to another? Would it apply to changes in the quantity at which an inactive ingredient is used? Would it apply to changes in the compositional specifications of an inactive ingredient?

The justification for this requirement suggested in the proposed rule was that some patients may be sensitive to certain inactive ingredients, and a change in NDC would flag for those patients and their pharmacists and health care providers that a drug's composition may have changed (or that some other characteristic identified in § 207.35 changed).

Upon careful consideration, we agree with those comments that challenged this justification. Paying attention to changes in NDCs would be an inexact way for patients, pharmacists, and health care providers to discover changes in inactive ingredients. As proposed and under this final rule, updates to drug listing information (including a new NDC) will be submitted each June and December, or sooner at the registrant's discretion. Thus, manufacturers will not be obligated to change an NDC immediately upon changing an inactive ingredient and update the NDC on their labels on a batch specific basis.

Comments pointed out that, particularly in the case of OTC monograph products, manufacturers currently have the flexibility to use certain inactive ingredients interchangeably. FDA's current guidance regarding the labeling of OTC drug products acknowledges this practice and includes formatting recommendations to accommodate the practice.

2

The proposed rule did not explain, for example, how the new NDC requirement would apply in a situation where the manufacturer of an OTC monograph product may have switched inactive ingredients in several different batches in the 6 months leading up to a semiannual listing update submission.

2

See the guidance for industry “Labeling OTC Human Drug Products—Questions and Answers,” December 2008, pp. 10-11, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs).

Rather than impose this burden on some manufacturers, and recognizing that ingredient labeling and reference to batch numbers are more useful and exact ways to ascertain a drug's composition, this final rule does not require a new NDC when a drug's inactive ingredients change.

(Comment 52) One group of comments expressed concern about the many situations in which a new NDC would be needed under the proposed rule. In addition to mentioning changes in inactive ingredients, the comments cited any addition to a drug's label or labeling, including the addition of stickers with delivery and handling instructions and “any material change to a drug's labeling or packaging insert” as things that should not warrant a new NDC. The comments emphasized the burden associated with changes to a drug's NDC.

(Response) Several changes in this final rule will reduce the number of occasions when a drug requires a new or additional NDC, compared to the proposed rule. See the response to comment 51 regarding changes to inactive ingredients. See our response to Comment 17 regarding the revised definition of “relabel” in the final rule to exclude the addition or modification of information affixed solely for purposes of delivery to a customer, customer identification, or inventory management. Under this final rule, changes or additions to a label that do not qualify as relabeling do not necessitate a drug listing submission and NDC under § 207.53. Section 207.35 of this final rule does not include “any material change” to a drug's labeling or package insert among the changes that necessitate a new NDC. Labeling changes are generally not included in new § 207.35. Some labeling changes will be incidental to the changes included in new § 207.35 (

e.g.,

a change to a drug's established or proprietary name), but labeling changes themselves do not trigger the need for a new NDC under this final rule. FDA has also determined that changes in Drug Master File numbers or Veterinary Master File numbers describing APIs, alone, should not necessitate new NDCs. Changes in APIs themselves,

i.e.,

a change in the identity of an API, will continue to necessitate new NDCs under new § 207.35.

(Comment 53) The Animal Health Institute noted that Animal Drug User Fee Act (ADUFA) fees are assessed for each animal drug NDC. This comment pointed out that manufacturers of animal drug products will be potentially charged twice for a single drug product due to a change in the NDC during a fiscal year or due to multiple listings for a single product required under this final rule. The comment urged FDA to exempt animal drug manufacturers from paying such extra product fees imposed by this final rule.

(Response) As noted in our response to Comment 52, several changes in this

final rule will reduce the number of occasions when a drug requires a new or additional NDC, compared to the proposed rule. Under ADUFA, the term “animal drug product” means each specific strength or potency of a particular active ingredient or ingredients in final dosage form marketed by a particular manufacturer or distributor, which is uniquely identified by the labeler code and product code portions of the NDC, and for which an animal drug application or a supplemental animal drug application has been approved. See section 739(3) of the FD&C Act. Because product fees are assessed under ADUFA for animal drug products meeting this definition, fees are not assessed for unfinished animal drugs or animal drugs that are not marketed. However, there may be instances where a change is made to a marketed animal drug product that necessitates a new NDC for that product during a single fiscal year, resulting in a new ADUFA product fee. This is an issue that has existed prior to this final rule.

(Comment 54) One comment asked whether a new NDC will be required when a manufacturer changes to a new supplier of an API or, relatedly, whether multiple NDCs would be needed if multiple suppliers of an API are indicated in an approval application for a finished drug product.

(Response) Section 207.35 of this final rule requires a new NDC when there is a change to any API. This provision includes changes from one API to another (

e.g.,

a change from acetaminophen to ibuprofen) and changes in the strength of an API. The provision does not encompass changes in suppliers and does not require multiple NDC product codes corresponding to multiple API suppliers.

(Comment 55) One comment requested clarification regarding when a change in drug product strength will require a new NDC (or when multiple strengths will require multiple NDCs). This comment distinguished between concentration and strength.

(Response) Section 207.35 of this final rule requires a new NDC if the strength of any API changes. The term “strength” is generally used to refer to the absolute quantity of API in a single unit dose (

e.g.,

250 milligrams (mg) per tablet). Concentration, on the other hand, refers to the amount of an ingredient per defined weight or volume of product (

e.g.,

1 mg/1 milliliter (mL)). Examples of multiple strengths requiring separate NDCs include 100 mg/tablet, 250 mg/tablet, 1 mg/1 mL, and 2 mg/2 mL. Each of these would require its own NDC if each is supplied as a unit dose. This is true even though the last two concentrations are equivalent.

(Comment 56) Some comments questioned whether two digits are sufficient for the package code segment of the NDC. Relatedly, some comments requested clarification regarding the need for a new NDC when changes are made to a drug's package size or type. For example, would a change from one type of plastic bottle to another necessitate a new NDC? Another comment argued that changes in medical gas packaging should not necessitate many new NDCs.

(Response) A 2-digit package code segment accommodates 100 different packaging configurations, counting “00” as one possibility.

There should be a separate package code for each package size. Therefore, if a package is enlarged to hold more of a drug product, it would need a new NDC.

A change in package configuration, such as a change from a bottle to a blister pack, would also require a new NDC.

Under new § 207.35(c), a new NDC (specifically a new package code segment) is needed for changes in the composition of packaging material that are significant enough so that the packaging type description previously submitted is no longer accurate. When submitting drug listing information electronically, registrants are currently prompted to identify the package type by selecting a choice from a drop down list. For example, “Bottle, Plastic” is currently one available selection in the drop down list. If a registrant originally described its packaging material using this term and later switched from one type of plastic bottle to another, there would be no need for a new NDC. But if a change in packaging material is more significant, from plastic bottle to glass bottle, for example, so that a new package type should be selected from the drop down list, FDA would require a new NDC with a new package code segment to accompany the revised listing under § 207.35(c). (This discussion pertains only to drug listing obligations. Please see the FDA guidance for industry on “Container Closure Systems for Packaging Human Drugs and Biologics” (May 1999, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs)) regarding filing requirements for changes to container closure systems in the case of drug products that are the subject of an approved application (NDA, abbreviated new drug application (ANDA), or BLA)).

Medical gases are generally packaged in tanks, canisters, or cylinders. A registrant listing a medical gas would choose the appropriate packaging type from the drop down list, populated with such terms, in our electronic drug establishment registration and listing system. We do not currently require more detail about the composition of a tank, canister, or cylinder in which a medical gas is packaged and would not require a listing update or a new NDC if the composition of a tank, canister, or cylinder changes. Therefore, we do not anticipate an unreasonable proliferation of NDCs associated with medical gas packaging under this final rule.

If a registrant exhausts all 100 package codes for a single product, that registrant may add a second product code, effectively making 100 more package codes available. This provision is reflected in § 207.35(c) of this final rule.

(Comment 57) One comment stated that many minor changes are made to a drug's packaging, such as resin composition and size optimization. This comment stated that these minor changes are already the subject of submissions to FDA, for example, as an annual report (submitted under § 314.81(b)(2)), a prior approval supplement to an NDA, or a changes-being-effected supplement. This comment implicitly questioned the need for new NDC package codes triggered by these changes.

(Response) Section 207.35(c) of this final rule requires new NDCs, specifically new package codes, when changes are made to a drug's package size or type. See our response to comment 56 regarding our interpretation of this requirement. We acknowledge that certain postapproval packaging changes are reported to an NDA, BLA, or ANDA consistent with current § 314.70 and FDA

http://www.fda.gov/Drugs

s guidance for industry “Container Closure Systems for Packaging Human Drugs and Biologics; Chemistry Manufacturing, and Controls Documentation” (May 1999, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs)) and to a new animal drug application (NADA) or an abbreviated new animal drug application (ANADA) consistent with current § 514.8 and FDA's guidance for industry “Chemistry, Manufacturing, and Controls Changes to an Approved NADA or ANDA” (May 2007, available on the Internet at

http://www.fda.gov/Drugs

under Guidances (Drugs)). These submissions, however, do not duplicate or satisfy the Agency's objectives behind drug listing and the use of the NDC to identify individual marketed drug products. These submissions also are

not made for drugs that are not subject to the new drug approval requirements.

3. What restrictions pertain to the use of the NDC? (§ 207.37)

Proposed § 207.37 set forth restrictions pertaining to the use of NDCs. These provisions are retained in the final rule with minor revisions. New § 207.37 clarifies that a product improperly bearing an NDC may be deemed to be misbranded. Additionally, new § 207.37 is not addressed only to “manufacturers, repackers, and relabelers.” Persons who are not subject to part 207 are cautioned against concluding that the restrictions stated in § 207.37 do not apply to them. Improper use of an NDC, as described in § 207.37, may result in a misbranding charge under the FD&C Act, whether or not the responsible party is generally subject to part 207.

(Comment 58) One comment agreed that NDCs should not appear in the labeling of dietary supplements, foods, and medical devices, but encouraged FDA to exercise enforcement discretion in this area. Other comments urged FDA to permit the use of NDCs on medical devices and medical foods. Others asked FDA to implement an alternative identification system for medical devices before finalizing this rule.

(Response) Section 207.37 of this final rule states that a product may be deemed to be misbranded if an NDC is used on the product but it is not subject to part 207. Since publication of the proposed rule, FDA has issued a final rule requiring UDIs on medical devices (78 FR 58786, September 24, 2013). Section 801.57 of that rule (21 CFR 801.57) generally prohibits the use of an NDC on the label of a medical device after the date on which it must bear a UDI.

The use of an NDC on the label of a product that is not regulated as a drug may confuse and mislead consumers and health care providers into believing FDA regulates the product as a drug. Any enforcement actions in this area will be subject to a determination that a product violates § 801.57 or is misbranded, or otherwise violates the FD&C Act.

(Comment 59) One comment argued against the proposed rule's prohibition against the use of NDCs on non-drug products and asked, if this prohibition is retained in the final rule, how long manufacturers of such products would have to remove NDCs from their labels.

(Response) Please see our response to comment 58 regarding the nature of § 207.37, specifically our clarification that the use of NDCs in the labeling of non-drug products may be handled as misbranding violations or as violations of § 801.57 as appropriate. See FDA's Unique Device Identifier rule (78 FR 58786) and any guidance FDA may issue regarding the compliance deadline for § 801.57. When an NDC in the labeling of a non-drug pro

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